Intermediates of benzoxazinone derivatives and preparation thereof

ABSTRACT

The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel β-aryl-α-oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereo-somers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.                    
     The present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.

This is a divisional application of 9/179,141, filed Oct. 26, 1998, nowU.S. Pat. No. 6,130,214.

FIELD OF INVENTION

The present invention relates to novel antiobesity andhypocholesterolermic compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutically acceptable compositions containing them.More particularly, the present invention relates to novelβ-aryl-α-oxysubstituted aylcarboxylic acids of the general formula (I),their derivatives, their analogs, their tautomeric forms, theirstereo-Somers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticallyacceptable compositions containing them.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their analogs, their derivatives, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, pharmaceutically acceptable solvates,novel intermediates and pharmaceutical compositions containing them.

The compounds of the present invention lower total cholesterol (TC);increase high density lipoprotein (HDL) and decrease low densitylipoprotein (LDL), which have beneficial effect on coronary heartdisease and atherosclerosis.

The compounds of general formula (I) are useful in reducing body weightand for the treatment and/or prophylaxis of diseases such ashypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertiglyceridemia, lowering of atherogenic lipoproteins, very lowdensity lipoprotein (VLDL) and LDL. The compounds of the presentinvention can be used for the treatment of certain renal diseasesincluding glomerulonephritis, glomerulosclerosis, nephrotic syndrome,hypertensive nephrosclerosis, retinopathy, and nephropathy The compoundsof general formula (I) are also useful for the treatment/prophylaxis ofinsulin resistance (type II diabetes), leptin resistance, impairedglucose tolerance, dyslipidemia, disorders related to syndrome X such ashypertension, obesity, insulin resistance, coronary heart disease, andother cardiovascular disorders. These compounds may also be useful asaldose reductase inhibitors, for improving cognitive functions indementia, treating diabetic complications, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy,pancreatitis, arteriosclerosis, xanthoma and for the treatment ofcancer. The compounds of the present invention are useful in thetreatment and/or prophylaxis of the above said diseases incombination/concomittant with one or more HMG CoA reductase inhibitorsor hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestymmine, colestipol, probucol.

BACKGROUND OF INVENTION

Atherosclerosis and other peripheral vascular diseases are the majorcauses effect the quality of life of millions of people. Therefore,considerable attention has been directed towards understanding theetiology of hypercholesterolemia and hyperlipidemia and the developmentof effective therapeutic strategies.

Hypercholesterolemia has been defined as plasma cholesterol level thatexceeds arbitrarily defined value called “normal” level. Recently, ithas been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as low density lipoprotein (LDL), intermediate densitylipoprotein (IDL), high density lipoprotein (HDL) and partially as verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

In CAD, generally “fatty streaks” in carotid, coronary and cerebralarteries, are found which are primarily free and esterified cholesterol.Miller et al, (Br. Med J., 282 (1981), 1741-1744) have shown thatincrease in HDL-particles may decrease the number of sites of stenosisin coronary arteries of humans, and high level of HDL-cholesterol mayprotect against the progression of atherosclerosis. Picardo et aL,(Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experimentthat HDL is capable of removing cholesterol from cells. They suggestthat HDL may deplete tissues of excess free cholesterol and transferthem to the liver (Macikinnon et al., J. Biol Chem. 261(1986),2548-2552). Therefore, agents that increase HDL cholesterol would havetherapeutic significance for the treatment of hypercholesterolernia andcoronary heart diseases (CHD).

Obesity is a disease highly prevalent in affluent societies and in thedeveloping world and which is a major cause of morbidity and mortality.It is a state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression has been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart idisease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

Diabetes and insulin resistance is yet another disease which severelyeffects the quality of life of a large population in the world. Ininsulin resistance is the diminished ability of insulin to exert itsbiological action across a broad range of concentrations. In insulinresistance, the body secretes abnormally high amounts of insulin tocompensate for this defect; failing which, the plasma glucoseconcentration inevitably rises and develops into diabetes. Among thedeveloped countries, diabetes mellitus is a common problem and isassociated with a variety of abnormalities including obesity,hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75: 809-817; N.Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988)66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renalcomplications (See Patent Application No. WO 95/21608). It is nowincreasingly being recognized that insulin resistance and relativehyperisulinemia have a contributory role in obesity, hypertension,atherosclerosis and type 2 diabetes melritus. The association of insulinresistance with obesity, hypertension and angina has been described as asyndrome having insulin resistance as the central pathogeniclink-Syndrome-X.

Hyperlipidemia is the primary cause of cardiovascular (CVD) and otherperipheral vascular diseases. High risk of CVD is related to the higherLDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein)seen in hyperlipidemia. Patients having glucose intolerance/insulinresistance in addition to hyperlipidemia have higher risk of CVD.Numerous studies in the past have shown that lowering of plasmatriglycerides and total cholesterol, in particular LDL and VLDL andincreasing HDL cholesterol help in preventing cardiovascular diseases.

Peroxisome proliferator activated receptors (PPAR) are members of thenuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ) hasbeen implicated in regulating differentiation of adipocytes(Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell,(1995) 83: 803-812), whereas the alpha (α) isoform of PPAR (PPARα)mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4:291-296) thereby resulting in reduction of circulating free fatty acidin plasma (Current Biol. (1995) 5: 618-621). PPARα agonists have beenfound useful for the treatment of obesity (WO 97/36579). It has beenrecently disclosed that the hypolipidemic effect is enhanced when themolecule has both PPARα and PPARγ agonist activity and are suggested tobe useful for the treatment of syndrome X (WO 97/25042). Synergismbetween the insulin sensitizer (PPARγ agonist) and HMG CoA reductaseinhibitor has been observed which may be useful for the treatment ofatherosclerosis and xanthoma. (EP 0 753 298).

It is known that PPARγ plays an important role in adipocytedifferentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR issufficient to cause complete terminal differentiation (Cell, (1994) 79,1147-1156) including cell cycle withdrawal. PPARγ is consistentlyexpressed in certain cells and activation of this nuclear receptor withPPARγ agonists would stimulate the terminal differentiation of adipocyteprecursors and cause morphological and molecular changes characteristicsof a more differentiated, less malignant state (Molecular Cell, (1998),465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997)94, 237-241) and inhibition of cancer expression of prostate cancertissue (Cancer Research (1998) 58, 3344-3352). This would be useful inthe treatment of certain types of cancer, which expresses PPARγ andcould leading to a quite nontoxic chemotherapy.

Leptin resistance is a condition wherein the target cells are unable torespond to leptin signal. This may give rise to obesity due to excessfood intake and reduced energy expenditure and cause impaired glucosetolerance, type 2 diabetes, cardiovascular diseases and such otherinterrelated complications. Kallen et al (Proc. Natl. Acad. Sci., (1996)93, 5793-5796) have reported that insulin sensitizers which perhaps dueto their PPAR agonist expression and therefore lower plasm leptinconcentrations. However, it has been recently disclosed that compoundshaving insulin sensitizing property also possess leptin sensitizationactivity. They lower the circulating plasma leptin concentrations byimproving the target cell response to leptin (WO 98/02159).

A few β-aryl-α-hydroxy propionic acids, their derivatives, and theiranalogs have been reported to be useful in the treatment ofhyperglycernia and hypercholesterolemia. Some of such compoundsdescribed in the prior art are outlined below:

i) U.S. Pat. No. 5,306,726; and WO 91/19702 disclose several3-aryl-2-hydroxy-propionic acid derivatives of general formula (II a)and (II b) as hypolipidemic and hypoglycemic agents.

Examples of these compounds are shown in formula (II c) and (II d)

ii) International Patent Applications, WO 95/03038 and WO 96/04260disclose compounds of formula (II e)

 wherein R^(a) represents 2-benzoxazolyl or 2-pyridyl and R^(b)represents CF₃, CH₂OCH₃ or CH₃. A typical example is(S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (II f).

iii) International Patent Application Nos. WO 94/13650, WO 94/01420 andWO 95/17394 disclose the compounds of general formula (II g)

A¹—X—(CH₂)_(n)—O—A²—A³—Y.R²  (II g)

 wherein A¹ represent aromatic heterocycle, A² represents substitutedbenzene ring and A³ represents moiety of formula (CH₂)_(m)—CH—(OR¹),wherein R¹ represents alkyl groups, m is an integer of the range of 1-5;X represents substituted or unsubstituted N; and Y represents C═O orC═S. R² represents OR³ where R³ may be hydrogen, alkyl, aralkyl, or arylgroup; and n represents an integer in the range of 2-6. An example ofthese compounds is shown in formula (II h)

SUMMARY OF THE INVENTION

With an objective to develop novel compounds for lowering cholesteroland reducing body weight with beneficial effects in the treatment and/orprophylaxis of diseases related to increased levels of lipids,atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucosetolerance, insulin resistance, insulin resistance leading to type 2diabetes and diabetic complications thereof, for the treatment ofdiseases wherein insulin resistance is the patho-physiologicalmechanism, for the treatment and/or prophylaxis of leptin resistance andcomplications thereof, hypertension, atherosclerosis and coronary arterydiseases with better efficacy, potency and lower toxicity, we focussedour research to develop new compounds effective in the treatment ofabove mentioned diseases. Effort in this direction has led to compoundshaving general formula (I).

The main objective of the present invention is therefore, to providenovel β-aryl-α-oxysubstituted alkycarboxylic acids, their derivatives,their analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts, and theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereo-isomers, their polymorphs,their pharmaceutically acceptable salts, and their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures which may have agonist activity against PPARα and/orPPARγ, and or unsubstituted or substituted inhibit HMG CoA reductase, inaddition to agonist activity against PPARα and/or PPARγ.

Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereo-isomers, their polymorphs,their pharmaceutically acceptable salts, and their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures having enhanced activities, without toxic effect or withreduced toxic effect.

Yet another objective of the present invention is to produce a processfor the preparation of novel β-aryl-α-oxysubstituted alkylcarboxylicacids of the formula (I) as defined above, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts and their pharmaceuticallyacceptable solvates.

Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or their mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

Another objective of the present invention is to provide novelintermediates, a process for their preparation and use of theintermediates in processes for preparation of β-aryl-α-oxysubstitutedalkyl carboxylic acids of formula (I), their derivatives, their analogs,their tautomers, their stereoisomers, their polymorphs, their salts andtheir pharmaceutically acceptable solvates.

DETAILED DESCRIPTION OF THE INVENTION

α-Oxysubstituted propionic acids, their derivatives, and their analogsof the present invention have the general formula (I)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵,and R⁶ when attached to carbon atom may be the same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl; orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,alkoxycarbonyl, aryloxy-carbonyl, aralkoxycarbonyl, amino, alkylaminowhich may be mono or dialkylamino group, arylamino, acylarnino,aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxy-carbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; W represents O, S or agroup NR¹¹; R¹¹ and the groups R⁵, and R⁶ when attached to nitrogen atommay be same or different and represent hydrogen, hydroxy, formyl orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino which may be mono ordialkylamino group, arylamino, aralkylamrino, aminoalkyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acidderivatives, or sulfonic acid derivatives; n is an integer ranging from1-4; Ar represents an unsubstituted or substituted divalent aromatic orheterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or unsubstituted or substituted aralkyl group orforms a bond with R⁸; R⁸ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, acyl group, or unsubstituted or substitutedaralkyl, or R⁸ forms a bond together with R⁷; R⁹ may be hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminiocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ may be hydrogenor unsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups; Yrepresents oxygen or NR¹², where R¹² represents hydrogen, orunsubstituted or substituted alkyl, aryl, hydroxy alkyl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyi groups; R¹⁰ and R¹² togethermay form a substituted or unsubstituted 5 or 6 membered cyclic structurecontaining carbon atoms, which may be unsubstituted or substitutedcontain one or more heteroatoms selected from oxygen, sulfuir ornitrogen; the linking group represented by —(CH₂)_(n)—O—may be attachedeither through nitrogen atom or carbon atom.

Suitable groups represented by R¹, R², R³, R⁴ and the groups, R⁵, R⁶when attached to carbon atom may be selected from hydrogen, halogen atomsuch as fluozine, chlorine, bromine, or iodine; hydroxy, cyano, nitro,formyl; substituted or unsubstituted (C₁-C₁₂)alkyl group, especially,linear or branched (C₁-C₆)alkyl group, such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-bulyl n-pentyl iso-pentyl hexyl andthe like; cyclo(C₃-C₆)alkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like, the cycloalkyl group may besubstituted; cyclo(C₃-C₆)alkoxy group such as cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, thecycloalkoxy group may be substituted; aryl group such as phenyl ornaphthyl, the aryl group may be substituted; aralkyl such as benzyl orphenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl groupmay be substituted and the substituted aralkyl is a group such asCH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like;heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryland the like, the heteroaryl group may be substituted; heterocyclylgroups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl and the like, the heterocyclyl group may be substituted;aralkoxy group such as benzyloxy, phenethyloxy, naphthyl-methyloxy,phenylpropyloxy and the like, the aralkoxy group may be substituted;hetero-arakyl group such as furanmethyl, pyridinemethyl, oxazolemethyl,oxazolemethyl and the like, the heteroaralkyl group may be substituted;aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and thelike, which may be substituted; alkoxycarbonyl such as methoxycarbonylor ethoxycarbonyl which may be substituted; aryloxycarbonyl group suchas or unsubstituted or substituted phenoxycarbonyl, naphthyloxycarbonyland the like; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthyl-methoxycarbonyl and the like, which maybe substituted; monoalkylamino group such as NHCH₃, NHC₂H₅, NHC₃H₇,NHC₆H₁₃ and the like, which may be substituted, dialkylamino group suchas N(CH₃)₂, NCH₃(C₂H₅), and the like, which may be substituted;alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl,ethoxyethyl and the like which may be substituted; aryloxyalkyl groupsuch as C₆H₅OCH₂, C₆H₅OCH₂CH₂, naphthyloxymethyl and the like, which maybe substituted; aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂and the like, which may be substituted; heteroar and heteroaralkoxy,wherein heteroaryl and heteroaralkyl moieties are as defined earlier andmay be substituted; aryloxy group such as phenoxy, naphthyloxy, thearyloxy group may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; amino group which may be substituted; amino(C₁-C₆)alkylwhich may be substituted; hydroxy(C₁-C₆)alkyl which may be substituted;(C₁-C₆)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy and the like which may be substituted; tbio(C₁-C₆)alkylwhich may be substituted; (C₁-C₆)alkylthio which may be substituted;acyl group such as acetyl, propanoyl or benzoyl, the acyl group may besubstituted; acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇,NHCOC₆H₅ which may be substituted; aralkoxycarbonylamino group such asNHCOOCH₂C₆H₅, NHCOOCH₂CH₂C₆H₅, N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅,NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄OCH₃ and the like, whichmay be substituted; aryloxycarbonylamio group such as NHCOOC₆H₅,NCH₃COOC₆H₅, NC₂H₅COOC₆H₅, NHCOOC₆H₄CH₃, NHCOOC₆H₄OCH₃ and the like,which may be substituted; alkoxy-carbonylamino group such as NHCOOC₂H₅,NHCOOCH₃ and the like, which may be substituted; carboxylic acid or itsderivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂,CONHPh and the like, the carboxylic acid derivatives may be substituted;acyloxy group such as OCOMe, OCOEt, OCOPh and the like, which may besubstituted; or sulfonic acid or its derivatives such as SO₂NH₂,SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like, the sulfonic acid derivativesmay be substituted.

When the groups represented by R¹, R², R³, R⁴, R⁵, and R⁶ aresubstituted, the substituents may be selected from halogen, hydroxy,nitro or unsubstituted or substituted groups selected from alkyl,cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy,alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives, or sulfonic acid or its derivatives.The substituents are defined as above.

It is preferred that the substituents on R¹-R⁶ represent halogen atomsuch as fluorine, chlorine, or bromine, hydroxy; or unsubstituted orsubstituted halogenated alkyl groups, the alkyl group is selected from agroup such as methyl, ethyl, isopropyl, n-propyl, or n-butyl; cycloalkylgroup such as cyclopropyl; aryl group such as phenyl; aralkyl group suchas benzyl; (C₁-C₃) alkoxy; beimyloxy, acyl or acyloxy groups;

Suitable R¹¹ and the groups R⁵, R⁶ when attached to nitrogen atom areselected from hydrogen, hydroxy, formyl; substituted or unsubstituted(C₁-C₁₂)alkyl group, especially, linear or branched (C₁-C₆)alkyl group,such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,t-butyl, n-pentyl, iso-pentyl, hexyl and the like; cyclo(C₃-₆)alkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike, the cycloalkyl group may be substituted; cyclo(C³-C₆)alkyloxygroup such as cyclopropyloxy, cyclobutyloxy, cyclo-pentyloxy,cyclohexyloxy and the like, the cycloalkoxy group may be substituted;aryl group such as phenyl or naphthyl, the aryl group may besubstituted; aralkyl such as benzyl or phenethyl, C₆H₅CH₂CH₂CH₂,naphthylmethyl and the like, the aralkyl group may be substituted andthe substituted aralkyl is a group such as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂,CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂and the like; heteroaryl group such aspyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl and the like, theheteroaryl group may be substituted; heterocyclyl groups such asaziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and thelike, the heterocyclyl group may be substituted; aralkoxy group such asbenzyloxy, phenethyloxy, naphthyl-methyloxy, phenylpropyloxy and thelike, the aralkoxy group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkylamino group such asC₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and the like, which may besubstituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonywhich may be substituted; aryloxycarbonyl group such as unsubstituted orsubstituted phenoxycarbonyl, naphthyloxycarbonyl and the like;aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl,naphthyl-methoxycarbonyl and the like, which may be substituted;monoalkylamino group such as NHCH₃, NHC₂H₅, NHC₃H₇, NHC₆H₁₃ and thelike, which may be substituted; dialkylamino group such as N(CH₃)₂,NCH₃(C₂H₅), and the like, which may be substituted; alkoxyalkyl groupsuch as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and thelike, which may be substituted; aryloxyalkyl group such as C₆H₅OCH₂,C₆H₅OCH₂CH₂, naphthyl-oxymethyl and the like, which may be substituted;aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like,which may be substituted; heteroaryloxy and heteroaralkoxy, whereinheteroaryl and heteroaralkyl moieties are as defined earlier and may besubstituted; aryloxy group such as phenoxy, naphthyloxy, the aryloxygroup may be substituted; arylamino group such as NHC₆H₅, NCH₃(C₆H₅),NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may be substituted; aminogroup which may be substituted; amino(C₁-C₆)alkyl which may besubstituted; hydroxy(C₁-C₆) alkyl which may be substituted;(C₁-C₆)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy and the like which may be substituted; thio(C₁-C₆)alkylwhich may be substituted; (C₁-C₆)alkylthio which may be substituted;acyl group such as acetyl, propanoyl or benzoyl, the acyl group may besubstituted; acylamino groups such as NHCOCH₃, NHCOC₂H₅, NHCOC₃H₇,NHCOC₆H₅ which may be substituted; carboxylic acid derivatives such asamides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh and the like,the carboxylic acid derivatives may be substituted; acyloxy group suchas OCOMe, OCOEt, OCOPh and the like which may be unsubstituted orsubstituted; sulfonic acid derivatives such as SO₂NH₂,SO₂NHMe, SO₂NMe₂,SO₂NHCF₃ and the like, the sulfonic acid derivatives may be substituted.

When the groups represented by R¹¹ and the groups R⁵, R⁶ attached tonitrogen are substituted, preferred substituents may be selected fromhalogen such as fluorine, chlorine; hydroxy, acyl, acyloxy, or aminogroups.

When the groups represented by R¹¹ and the groups R⁵, R⁶ are attached tonitrogen atom, R¹-R⁴ are same as defined earlier.

The group represented by Ar includes substituted or unsubstituted groupsselected from divalent phenylene, naphthylene, pyridyl, quinolinyl,benzofuryl, benzoxazolyl, benzo-thiazolyl, indolyl, indolinyl,azaindolyl, aindolinyl, indenyl, dihydrobenzofuryl, benzo-pyranyl,dihydrobenzopyranyl, pyrazolyl and the like. The substituents on thegroup represented by Ar include linear or branched or unsubstituted orsubstituted halogenated (C₁-C₆)alkyl, or unsubstituted or substitutedhalogenated (C₁-C₃)alkoxy, halogen, acyl, amino, acylamino, thio,carboxylic and sulfonic acids and their derivatives. The substituentsare defined as they are for R¹-R⁴.

It is more preferred that Ar represents a substituted or unsubstituteddivalent, phenylene, naphthylene, benzofuryl, indolyl, indolinyl,quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolylgroups.

It is still more preferred that Ar is represented by divalent phenyleneor naphthylene, which may be unsubstituted or substituted by methyl,halomethyl, methoxy or halomethoxy groups.

Suitable R⁷ includes hydrogen, lower alkyl groups such as methyl, ethylor propyl; hydroxy, (C₁-C₃)alkoxy; halogen atom such as fluorine,chlorine, bromine, or iodine; aralkyl such as benzyl, or phenethyl,which may be unsubstituted or substituted with halogen, hydroxy,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, benzyloxy, acetyl, acetyloxy groups,preferably with hydroxy, halogen, (C₁-C₃)alkyl or alkoxy (C₁-C₃), or R⁷together with R⁸ represent a bond.

Suitable R⁸ may be hydrogen, lower alkyl groups such as methyl, ethyl orpropyl; hydroxy, (C₁-C₃)alkoxy; halogen atom such as fluorine, chlorine,bromine, or iodine; acyl group such as linear or branched (C₂-C₁₀)acylgroup such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and thelike; aralkyl such as benzyl, phenethyl, which may be unsubstituted orsubstituted with halogen, hydroxy, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,benzyloxy, acetyl, acetyloxy groups, preferably with hydroxy, halogen,(C₁-C₃)alkyl or (C₁-C₃) alkoxy, or R⁸ together with R⁷ forms a bond.

It is preferred that R⁷ and R⁸ represent hydrogen atom or R⁷ and R⁸together represent a bond.

Suitable groups represented by R⁹ may be selected from hydrogen, linearor branched (C₁-C₁₆)alkyl, preferably (C₁-C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like, which may be substituted; (C₃-C₇)cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like,the cycloalkyl group may be substituted; aryl group such as phenyl,naphthyl, the aryl group may be substituted; heteroaryl group such aspyridyl, thienyl, furyl and the like, the heteroaryl group may besubstituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazol-emethyl, oxazolthyl and the like, the heteroaralkyl group may besubstituted; aralkyl group wherein the aryl group is as defined earlierand the alkyl moiety may contain C₁-C₆ atoms such as benzyl, phenethyland the like, the aralkyl group may be substituted; heterocyclyl groupsuch as aziridinyl, pyrrolidinyl, piperidinyl and the like, theheterocyclyl group may be substituted; (C₁-C₆)alkoxy(C₁-C₆)alkyl groupsuch as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and thelike, the alkoxyalkyl group may be substituted; aryloxyalkyl group suchas C₆H₅OCH₂, C₆H₅OCH₂CH₂, naphthyloxymethyl, naphthyl-oxyethyl and thelike, which may be substituted; linear or branched (C₂-C₁₆)acyl groupsuch as acetyl, propanoyl, isopropanol, butanoyl, benzoyl, octanoyl,decanoyl and the like which may be substituted; (C₁-C₆)alkoxycarbonyl,the alkyl group may be substituted; aryloxy-carbonyl such asphenoxycarbonyl, naphthyloxycarbonyl, the aryl group may be substituted;(C₁-C₆)alkylaminocarbonyl the alkyl group may be substituted; andarylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl, the aryl moietymay be substituted. The substituents may be selected from halogen,hydroxy, formyl or nitro or unsubstituted or substituted groups selectedfrom alkyl, cycloalkyl alkoxy, cycloalkoxy, aryl, aralkyl,aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy,hydroxyalkyl, amino, acylamino, aryl-amino, aminoalkyl, aryloxy,alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid or its derivatives, or sulfonic acid or its derivatives.These groups are as defined above.

Suitable groups represented by R¹⁰ may be selected from hydrogen,substituted or unsubstituted linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl group such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like;(C₃-C₇)cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and thelike, the cycloalkyl group may be substituted; aryl group such asphenyl, naphthyl, the aryl group may be substituted; heteroaryl groupsuch as pyridyl, thienyl, furyl and the like, the heteroaryl group maybe substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may besubstituted; aralkyl group such as benzyl and phenethyl, the aralkylgroup may be substituted; heterocyclyl group such as aziridinyl,pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may besubstituted. The substituents on R¹⁰ may be selected from the same groupof R¹-R⁴ and are as defined above.

Suitable groups represented by R¹² may be selected from hydrogen,substituted or unsubstituted linear or branched (C₁-C₁₆)alkyl,preferably (C₁-C₁₂)alkyl; hydroxy (C₁-C₆) alkyl which may besubstituted; aryl group such as phenyl, naphthyl and the like, which maybe substituted; aralkyl group such as benzyl and phenethyl and the like,which may be substituted; heterocyclyl group such as aziridinyl,pyrrolidinyl, piperidinyl, and the like which may be substituted;heteroaryl group such as pyridyl, thienyl, furyl and the like, which maybe substituted; and heteroaralkyl group such as furanmethyl,pyridinemethyl, oxazolemethyl, oxazolethyl and the like, which may besubstituted.

The cyclic structure formed by R¹⁰ and R¹² may be a substituted orunsubstituted 5 or 6 membered cyclic structure containing carbon atomswhich may be unsubstituted or substituted contains one or twoheteroatoms selected from oxygen, nitrogen or sulfur.

Suitable ring structures formed by R¹⁰ and R¹² together may be selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl,diazolinyl and the like.

Suitable substituents on the cyclic structure formed by R¹⁰ and R¹²taken together may be selected from halogen, hydroxy, alkyl, oxo,aralkyl and the like.

Suitable n is an integer ranging from 1 to 4, preferably n represents aninteger 1 or 2.

Pharmaceutically acceptable salts forming part of this invention includesalts of the carboxylic acid moiety such as alkali metal salts like Li,Na, and K salts; alkaline earth metal salts like Ca and Mg salts; saltsof organic bases such as lysine, arginine, guanidine, diehanolamine,choline, tromethamine and the like; ammonium or substituted ammoniumsalts, and aluminum salts. Salts may include acid addition salts whereappropriate which are, sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,succinates, palmoates, methanesulphonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

Particularly useful compounds according to the present inventioninclude:

Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-propenoate;

(±)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(+)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(−)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

[2R,N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide;

[2S,N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylthyl)propanamide;

(+)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoic acid and its salts;

(−)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-diydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

(±)-Ethyl2-phenoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-propenoate;

(±)-Ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(+)-Ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]-ethoxy]phenyl]propanoate;

(−)-Ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

(+)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and salts;

(−)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

(±)-Methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(±)2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(+)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(±)-Methyl2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxyl]phenyl]propanoate;

(±)2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tethydro-2-quinazolinyl]methoxy]phenyl]propanoicacid;

(+)-2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid;

(−)-2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid;

(±)-Methyl2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxylphenyl]propanoate;

(±)-2-Ethoxy-3-(4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(±)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(±)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl ]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(+)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid and its salts;

(±)-Methyl2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[3-ethyl-4-oxo1,2,3,4-tetrahydro-2quiazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(+)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Ethoxy-3-[4-[[3-ethy-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(±)-Methyl-2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and salts;

(+)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and salts;

(−)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and salts;

(±)-Methyl2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(±)-2-Phenoxy-3-[4-[[4-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(+)-2-Phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(±)-Methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(+)-Methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(−)-Methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate;

(±)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(+)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(−)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid and its salts;

(±)-Ethyl2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(+)-Ethyl2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(−)-Ethyl2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(±)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]propanoicacid and its salts;

(+)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]propanoicacid and its salts;

(−)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

(±)-Ethyl2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(+)-Ethyl2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate,

(−)-Ethyl2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate;

(±)-2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and it s salts;

(+)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts; and

(−)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid and its salts;

According to a feature of the present invention, the compound of formula(I) where R⁷ and R⁸ together represent a bond, Y represents oxygen atom,R¹, R², R³, R⁴, R⁵, R⁶, X, W, R⁹, R¹⁰, n and Ar are as defined earlier,may be prepared by any of the following routes shown in Scheme-I below

Route (1): The reaction of a compound of the general formula (IIIa)where all other symbols arc as defined earlier, with a compound offormula (IIIb), where R⁹, R¹⁰ are as defined earlier excluding hydrogenatom and R¹³ represents (C₁-C₆)alkyl group, to yield a compound ofgeneral formula (I) defined above may be carried out in the presence ofa base such as alkali metal hydrides like Nail, KH or organolithiumnslike CH₃Li, BuLi and the like or alkoxides such as NaOMc, NaOEt, BuO⁻K⁺or mixtures thereof. The reaction may be carried out in the presence ofsolvents such as THF, dioxane, DMF, DMSO, DME and the like or mixturesthereof. HMPA may be used as cosolvent. The reaction temperature mayrange from −78° C. to 50° C., preferably at a temperature in the rangeof −10° C. to 30° C. The compound of general formula (IIIb) may beprepared by Arbuzov reaction.

The intermediate of formula (IIIa) wherein W represents nitrogen atomand the linker group —(CH₂)_(n)— is attached through carbon atom and theprocess for its preparation have been disclosed in the Copendingapplication Ser. No. 08/982,911.

Alternatively, the compound of formula (I) may be prepared by reactingthe compound of formula (IIIa) where all symbols are as defined earlierwith Wittig reagents such as Hal⁻Ph₃P⁺CH—(OR⁹)CO₂R¹⁰ under similarreaction conditions as described above.

Route (2): The reaction of a compound of the general formula (IIIa)where all other symbols are as defined earlier, with a compound offormula (IIIc) where R⁸ represents a hydrogen atom and all other symbolsare as defined above to produce a compound of formula (I) defined abovemay be carried out in the presence of a base. The nature of the base. isnot critical. Any base normally employed for aldol condensation reactionmay be employed; bases like metal hydride such as NaH, or KH; metalalkoxides such as NaOMe, K⁺BuO⁻, or NaOEt; metal amides such as LiNH₂,or LiN(iPr)₂ may be used. Aprotic solvent such as THF, ether, or dioxanemay be used. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar, or He andthe reaction is more effective under anhydrous conditions. Temperaturein the range of −80° C. to 35° C. may be used. The β-hydroxy productinitially produced may be dehydrated under conventional dehydrationconditions such as treating with PTSA in solvents such as benzene ortoluene. The nature of solvent and dehydrating agent is not critical.Temperature in the range of 20° C. to reflux temperature of the solventused may be employed, preferably at reflux temperature of the solvent bycontinuous removal of water using a Dean Stark water separator.

Route (3): The reaction of compound of formula (IIIe) where all symbolsare as defined earlier and L¹ represents a leaving group such as halogenatom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonateand the like, with a compound of formula (IIId) where R⁷ and R⁸ togetherrepresent a bond, and all other symbols are as defined earlier toproduce a compound of the formula (I) defined above may be carried outin the presence of aprotic solvents such as THF, DMF, DMSO, DME and thelike or mixtures thereof. The reaction may be carried out in an inertatmosphere which may be maintained by using inert gases such as N₂, Ar,or He. The reaction may be effected in the presence of a base such asK₂CO₃, Na₂CO₃ or NaH or mixtures thereof. Acetone may be used as solventwhen Na₂CO₃ or K₂CO₃ is used as a base. The reaction temperature mayrange from 0° C.-120° C., preferably at a temperature in the range of30° C.-100° C. The duration of the reaction may range from 1 to 24hours, preferably from 2 to 12 hours. The compound of formula (IIId) canbe prepared according to known procedure by a Wittig Horner reactionbetween the hydroxy protected aryl aldehyde such as benzyloxy arylaldehyde and the compound of formula (IIIb), followed by deprotection.

Route (4): The reaction of a compound of general formula (IIIf) whereall symbols are as defined earlier with a compound of general formula(IIIg) where R⁷, R⁸ together represent a bond, and all symbols are asdefined earlier and L¹ is a leaving group such as halogen atom,p-toluenesulfonate, methanesulfonate, trifiuoromethanesulfonate and thelike, preferably a halogen atom to produce a compound of general formula(I) defined above where the linker group —(CH₂)_(n)—O—is attached tonitrogen atom may be carried out in the presence of solvents such asDMSO, DMF, DME, THF, dioxane, ether and the like or a combinationthereof. The reaction may be carried out in an inert atmosphere whichmay be maintained by using inert gases such as N₂, Ar, He. The reactionmay be effected in the presence of a base such as alkis like sodiumhydroxide or potassium hydroxide, alkali metal carbonates like sodiumcarbonate or potassium carbonate; alkali metal hydrides such as sodiumhydride or potassium hydride; organometallic bases like n-butyl lithium,alkali metal amides like sodamide or mixtures thereof. The amount ofbase may range from 1 to 5 equivalents, based on the amount of thecompound of formula (IIIf), preferably the amount of base ranges from 1to 3 equivalents. Phase transfer catalysts such as tetraalkylammoniumhalide or hydroxide may be added. The reaction may be caried out at atemperature in the range of 0° C. to 150° C., preferably at atemperature in the range of 15° C. to 100° C. The duration of thereaction may range from 0.25 to 48 hours, preferably from 0.25 to 12hours.

Route (5): The reaction of compound of general formula (IIIh) where allsymbols are as defined earlier, with a compound of general formula(IIId) where R⁷ and R⁸ together represent a bond, and all other symbolsare as defined earlier to produce a compound of formula (I) definedabove may be carried out using suitable coupling agents such asdicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such asPPh₃/DEAD and the like. The reaction may be carried out in the presenceof solvents such as THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile,carbontetrachloride and the like. The inert atmosphere may be maintainedby using inert gases such as N₂, Ar, or He. The reaction may be effectedin the presence of DMAP, HOBT and they may be used in the range of 0.05to 2 equivalents, preferably 0.25 to 1 equivalents. The reactiontemperature may be in the range of 0° C. to 100° C., preferably at atemperature in the range of 20° C. to 80° C. The duration of thereaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.

Route (6): The reaction of compound of general formula (IIIi) where allsymbols are as defined earlier, with a compound of formula (IIIj) whereR¹⁴ represents lower alkyl group, R⁷ and R⁸ together represent a bond,and all other symbols are as defined earlier to produce a compound offormula (I) wherein the linker group —CH₂)_(n)—O—is linked throughcarbon atom may be carried out in neat or in the presence of solventssuch as THF, CHCl₃, benzene, toluene, hexane, dioxane and the like ormixture thereof. The reaction may be carried out at a temperature in therange of 0° C. to 250° C. preferably at a temperature in the range of10° C. to 150° C. The reaction may be carried out in the presence of anacid or a base. The selection of acid or base is not critical. Theexamples of such acids include H₂SO₄, HCl, pTsOH, PPE (polyphosphoricethyl ester) and the like. Examples of bases include pyrrolidine,lutidine, triethyl amine, diisopropylethyl amine, piperidine and thelike. The reaction may be carried out in an inert atmosphere which maybe maintained by using inert gases such as N₂, Ar or He. The duration ofthe reaction may range from 0.25 to 24 h preferably, from 1 to 12 h.

Route (7): The reaction of a compound of formula (IIIk) where allsymbols are as defined earlier with a compound of formula (IIIl) whereR⁹═R¹⁰ and are as defined earlier excluding hydrogen atom to produce acompound of the formula (I) where R⁷ and R⁸ together represent a bondmay be carried out neat in the presence of a base such as alkali metalhydrides like NaH, or KH or organolithiums like CH₃Li, BuLi and the likeor alkoxides such as NaOMe, NaOEt, K⁺BuO⁻ and the like or mixturesthereof. The reaction may be carried out in the presence of aproticsolvents such as THF, dioxane, DMF, DMSO, DME and the like or mixturesthereof. HMPA may be used as cosolvent. The reaction temperature mayrange from −78° C. to 100° C., preferably at a temperature in the rangeof −10° C. to 50° C.

Route (8): The reaction of compound of general formula (IIIm), where R⁷and R⁸ together represent a bond and all other symbols are as definedearlier with a compound of general formula (IIIn) where R¹⁴ representslower alkyl group and where all symbols are as defined earlier toproduce a compound of general formula (I), where —(CH₂)_(n)—O—linkergroup is attached through nitrogen atom and all other symbols are asdefined earlier may be carried out in neat or in the presence ofsolvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSOand the like or mixtures thercof The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be carried out at a temperature in therange of 50° C. to 200° C., preferably at a temperature in the range of60° C. to 180° C. The reaction may be effected in the presence or inabsence of a base or an acid. The nature of the base or the acid is notcritical. Examples of such bases include organic bases such as pyridine,lutidine, triethyl amine, diisopropylethyl amine and the like, metalcarbonates such as K₂CO₃, and Na₂CO₃. Examples of acids include organicacids such as AcOH, C₂H₅COOH butyric acid, trifluoroacetic acid,p-toluenesulfonic acid, benzenesulfonic acid and the like, mineral acidssuch as HCl, HBr etc. The duration of the reaction may range from 0.25to 48 hours, preferably from 0.50 to 18 hours.

In yet another embodiment of the present invention, the compound ofgeneral formula (I) where all symbols are as defined earlier, R⁷represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, orunsubstituted or substituted aralkyl group; R⁸ represents hydrogenatomn, hydroxy, alkoxy, halogen, lower alkyl; or unsubstituted orsubstituted aralkyl or acyl group; and Y represents an oxygen atom canbe prepared by one or more of the processes shown in Scheme-II below:

Route (9): The reduction of compound of the formula (IVa) whichrepresents a compound of formula (I) where R⁷ and R⁸ together representa bond, Y represent oxygen and all other symbols are as defined earlier,obtained as described earlier in Scheme-I, to yield a compound of thegeneral formula (I) where R⁷ and R⁸ each represent hydrogen atom and allsymbols are as defined earlier, may be carried out in the presence ofgaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like.Mixtures of catalysts may be used. The reaction may also be conducted inthe presence of solvents such as dioxane, acetic acid, ethyl acetate andthe like. A pressure between atmospheric pressure and 80 psi may beemployed The catalyst may be preferably 5-10% Pd/C and the amount ofcatalyst used may range from 50-300% w/w. The reaction may also becarried out by employing metal solvent reduction such as magnesium inalcohol or sodium amalgam in alcohol, preferably methanol. Thehydrogenation may be carried out in the presence of metal catalystscontaining chiral ligands to obtain a compound of formula (I) inoptically active form. The metal catalyst may contain Rhodium,Ruthenium, Indium and the like. The chiaal ligands may preferably bechiral phosphines such as 2,3-bis(diphenylphosphino)butane,1,2-bis(diphenyl-phosphino thane, 1,2-bis(2-methoxyphenylphosphino)ethane,2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and the like. Any suitablechiral catalyst may be employed which would give required optical purityof the product (I) (Ref: Principles of Asymmetric Synthesis, Tet. Org.Chem. Series Vol 14, pp 311-316, Ed. Baldwin J. E.).

Route (10): The reaction of compound of formula (IVb) where R¹⁰ is asdefined earlier excluding hydrogen atom and all other symbols are asdefined earlier and L² is a leaving group such as halogen atom with acompound of general formula (IVc), where R⁹ is as defined earlierexcluding hydrogen atom to produce a compound of the formula (I) may becarried out in the presence of solvents such as THF, DMF, DMSO, DME andthe like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar, or He. The reaction may be effected in the presence of a basesuch as KOH, NaOH, NaOMe, NaOEt, K⁺BuO⁻ or NaH or mixtures thereof.Phase transfer catalysts such as tetraalkylammonium halides orhydroxides may be employed. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-100° C.The duration of the reaction may range from 1 to 12 hours, preferablyfrom 2 to 6 hours. The compound of general formula (IVb) where thelinker group —(CH₂)_(n)—O—is attached through carbon atom and itspreparation has been disclosed in the copending U.S. application Ser.No. 08/982,911.

Route (11): The reaction of compound of formula (IIIe) defined earlierwith a compound of formula (IIId) where all symbols are as definedearlier to produce a compound of the formula (I) may be carried out inthe presence of solvents such as THF, DMF, DMSO, DME and the like ormixtures thereof The reaction,may be carried out in an inert atmospherewhich is maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as K₂CO₃, Na₂CO₃or NaH or mixtures thereof Acetone may be used as a solvent when K₂CO₃or Na₂CO₃ is used as a base. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-80° C.The duration of the reaction may range from 1 to 24 hours, preferablyfrom 2 to 12 hours. The compound of formula (IIId) may be prepared byWittig Homer reaction between the protected hydroxyaryl aldehyde andcompound of formula (IIIb) followed by reduction of the double bond anddeprotection. Alternatively, the compound of formula (IIId) may beprepared by following a procedure disclosed in WO 94/01420.

Route (12): The reaction of compound of general formula (IIIh) definedearlier with a compound of general formula (IIId) where all symbols areas defined earlier to produce a compound of the formula (I) where allsymbols are as defined above may be carried out using suitable couplingagents such as dicyclohexyl urea,triarylphosphine/dialkylaza-dicarboxylate such as PPh₃/DEAD and thelike. The reaction may be carried out in the presence of solvents suchas THF, DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbon tetrachlorideand the like. The inert atmosphere may be maintained by using inertgases such as N₂, Ar, or He. The reaction may be effected in thepresence of DMAP, HOBT and they may be used in the range of 0.05 to 2equivalents, preferably 0.25 to 1 equivalents. The reaction temperaturemay be in the range of 0° C. to 100° C., preferably at a temperature inthe range of 20° C. to 80° C. The duration of the reaction may rangefrom 0.5 to 24 hours, preferably from 6 to 12 hours.

Route (13): The reaction of compound of formula (IVd) where all othersymbols are as defined earlier with a compound of formula (IVe) where R⁹is as defined earlier excluding hydrogen atom and L² is a leaving groupsuch as a halogen atom to produce a compound of formula (I) may becarried out in the presence of solvents such as THF, DMF, DMSO, DME andthe like. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar or He. The reaction may be effected in the presence of abase such as KOH, NaOH, NaOMe, K⁺BuO⁻, NaH and the like. Phase transfercatalyst such as tetraalkylammonium halides or hydroxides may beemployed. The reaction temperature may range from 20° C. to 150° C.,preferably at a temperature in the range of 30 ° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 6 hours.

The compound of formula (IVd) represents compound of formula (I) whereR⁹ is hydrogen atom, Y is oxygen atom and all other symbols are asdefined earlier.

The compound of general formula (IVd) may also be prepared from compoundof formula (IVb), described in copending U.S. application Ser. No.08/982,911 where L² is a halogen atom by reacting with formamide in thepresence of water. Alternatively, it can be prepared from (IVa) byheating with aqueous alkali to 20° C. to 100° C. followed byreesterification of the hydrolysed acid.

Route (14): The reaction of a compound of the general formula (IIIa) asdefined above with a compound of formula (IIIc) where R⁸ is hydrogen andall other symbols are as defined earlier to produce a compound offormula (I) may be carried out under conventional conditions. The baseis not critical. Any base normally employed for aldol condensationreaction may be employed, metal hydride such as NaH, or KH, metalalkoxides such as NaOMe, KOtbu, or NaOEt; metal amides such as LiNH₂, orLiN(iPr)₂. Aprotic solvent such as THF may be used. Inert atmosphere maybe employed such as argon and the reaction is more effective underanhydrous conditions. Temperature in the range of −80° C. to ₂₅° C. maybe used. The β-hydroxyaldol product may be dehydroxylated usingconventional methods, conveniently by ionic hydrogenation technique suchas by treating with a trialkyl silane in the presence of an acid such astrifluoroacetic acid. Solvent such as CH₂Cl₂ may be used. Favorablyreaction proceeds at 25° C. Higher temperature may be employed if thereaction is slow.

Route (15): The reaction of a compound of general formula (IIIf) whereall symbols are as defined earlier with a compound of general formula(IIIg) where all symbols are as defined earlier and L¹ is a leavinggroup such as halogen atom, p-toluenesulfonate, methanesulfonate,trifluoromethanesulfonate and the like, preferably a halogen atom, toproduce a compound of general formula (I) defined above where the—(CH₂)_(n)—O—is attached through nitrogen atom may be carried out in thepresence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and thelike or a combination thereof The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar, or He. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide or potassium hydroxide; alkalimetal carbonates like sodium carbonate or potassium carbonate; alkalimetal hydrides such as sodium hydride or potassium hydride;organometallic bases like n-butyl lithium; alkali metal amides likesodamide or mixtures thereof. The amount of base may range from 1 to 5equivalents, based on the amount of the compound of formula (IIIf),preferably the amount of base ranges from 1 to 3 equivalents. Thereaction may be carried out at a temperature in the range of 0° C. to150° C., preferably at a temperature in the range of 15° C. to 100° C.The duration of the reaction may range from 0.25 to 24 hours, preferablyfrom 0.25 to 6 hours.

Route (16): The reaction of compound of general formula (IIIi) where allsymbols are as defined earlier, with a compound of formula (IIIj) whereR¹⁴ represents lower alkyl group and all other symbols are as definedearlier to produce a compound of formula (I) where the linker group—(CH₂)_(n)—O—is attached through carbon atom and all other symbols areas defined earlier, may be carried out in neat or in the presence ofsolvents such as THF, CHCl₃, benzene, toluene, hexane, dioxane and thelike or mixture thereof. The reaction may be carried out at atemperature in the range of 0° C. to 250° C. preferably at a temperaturein the range of 10° C. to 150° C. The reaction may be carried out in thepresence of an acid or a base. The selection of acid or base is notcritical. The examples of such acids include H₂SO₄, HCl, pTsOH, PPE(polyphosphoric ethyl ester) and the like. Examples of bases includepyrrolidine, piperidine and the like. The reaction may be carried out inan inert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The duration of the reaction may range from 0.25 to 24 hpreferably, from 1 to 12 h.

The compound of general formula (IIIj), where all the symbols are asdefined earlier may be prepared by a process which comprises, reacting acompound of the general formula (IVh)

(R¹⁴O)₂CR⁵—(CH₂)_(n)—L¹  (IVh)

where R¹⁴ is a lower alkyl group and all other symbols are as definedearlier with a compound of general formula (IIId) where R⁷, R⁸, R⁹, R¹⁰and Ar are as defined earlier.

The reaction of compound of formula (IVh) with compound of formula(IIId) to produce a compound of the formula (IIIj) may be carried out inthe presence of solvents such as THF, DMF, DMSO, DME and the like ormixtures thereof. The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar or He. Thereaction may be effected in the presence of a base such as K₂CO₃, Na₂CO₃or NaH or mixtures thereof. The reaction temperature may range from 20°C.-120° C., preferably at a temperature in the range of 30° C.-80° C.The duration of the reaction may range from 1-12 hours, preferably from2 to 6 hours.

Route (17): The conversion of compound of formula (IVf) where allsymbols are defined above to a compound of formula (I) may be carriedout either in the presence of a base or an acid and the selection ofbase or acid is not critical. Any base normally used for hydrolysis ofnitrile to acid may be employed; metal hydroxides such as NaOH, or KOHin an aqueous solvent or any acid normally used for hydrolysis ofnitrile to ester may be employed such as dry HCl in an excess of alcoholsuch as methanol, ethanol, propanol etc. The reaction may be carried outat a temperature in the range of 0° C. to reflux temperature of thesolvent used, preferably at a temperature in the range of 25° C. toreflux temperature of the solvent used. The duration of the reaction mayrange from 0.25 to 48 hrs.

Route (18): The reaction of a compound of formula (IVg) where R¹⁰ is asdefined earlier excluding hydrogen atom and all other symbols are asdefined earlier with a compound of formula (IVc) where R⁹ is as definedearlier excluding hydrogen atom to produce a compound of formula (I) (bya rhodium carbenoid mediated insertion reaction) may be carried out inthe presence of rhodium (II) salts such as rhodium (II) acetate. Thereaction may be carried out in the presence of solvents such as benzene,toluene, dioxane, ether, THF and the like or a combination thereof orwhen practicable in the presence of R⁹OH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar or He. The duration of the reaction may range from 0.5 to24 h, preferably from 0.5 to 6 h.

Route (19): The reaction of compound of general formula (IIIm), where R⁷and R⁸ are as defined earlier, and all other symbols are as definedearlier with a compound of general formula (IIIn) where R¹⁴ representslower alkyl group and all other symbols are as defined earlier toproduce a compound of general formula (I), where —(CH₂)_(n)—O—linkergroup is attached through nitrogen atom and all other symbols are asdefined earlier may be carried out in neat or in the presence ofsolvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSOand the like or mixtures thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar or He. The reaction may be carried out at a temperature in therange of 50° C. to 200° C., preferably at a temperature in the range of60° C. to 180° C. The reaction may be effected in the presence or inabsence of a base or an acid. The nature of the base or the acid is notcritical. Examples of such bases include organic bases such as pyridine,lutidine, triethyl amine, diisopropyl-ethyl amine and the like, metalcarbonates such as K₂CO₃, Na₂CO₃. Examples of acids include organicacids such as AcOH, C₂H₅COOH, butyric acid, trifluoroacetic acid,p-toluenesulfonic acid, benzenesulfonic acid and the like, mineral acidssuch as HCI, HBr etc. The duration of the reaction may range from 0.25to 48 hours, preferably from 0.50 to 18 hours.

The compound of general formula (I) where R¹⁰ represents hydrogen atommay be prepared by hydrolysing a compound of formula (I) where R¹⁰represents all groups defined earlier except hydrogen using conventionalmethods. The hydrolysis may be carried out in the presence of a basesuch as Na₂CO₃ and a suitable solvent such as methanol, ethanol and thelike or mixtures thereof The reaction may be carried out at atemperature in the range of 20-40° C., preferably at 25-30° C. Thereaction time may range from 2 to 12 h, preferably from 4 to 8 h.

The compound of general formula (I) where Y represents oxygen and R¹⁰represents hydrogen or a lower alkyl group may be converted to compoundof formula (I), where Y represents NR¹⁰ by reaction with appropriateamines of the formula NHR¹²R¹², where. R¹⁰ and R¹² are as definedearlier. Suitably, the compound of formula (I) where YR¹⁰ represents OHmay be converted to acid halide, preferably YR¹⁰═Cl, by reacting withappropriate reagents such as oxalyl chloride, thionyl chloride and thelike, followed by treatment with amines of formula NHR₁₀R₁₂ where R₁₀and R₁₂ are as defined earlier. Alternatively, mixed anhydrides may beprepared from compound of formula (I) where YR¹⁰ represents OH and allother symbols are as defined earlier by treating with acid halides suchacetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoylchloride and the like. The reaction may be carried out in the presenceof suitable base such as pyridine, triethylamine, diisopropyl ethylamine and the like. Solvents such as halogenated hydrocarbons likeCHCl₃, or CH₂Cl₂; hydrocarbons such as benzene, toluene, xylene and thelike may be used. The reaction may be carried out at a temperature inthe range of −40° C. to 40° C., preferably at a temperature in the rangeof 0° C. to 20° C. The acid halide or mixed anhydride thus prepared mayfurther be treated with appropriate amines of formula NHR¹⁰R¹² where R¹⁰and R¹² are as defined earlier.

In another embodiment of the present invention the novel intermediate offormula (IVf)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵,and R⁶ when attached to carbon atom may be same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl; orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, hetero-aryloxy, heteroaralkyl, heteroaralkoxy, acyl,acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino,alkylamino which may be mono or dialkylamino group, arylamino,acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl,aryloxyalkyl, aralkoxy-alkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonyl-amino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; W represents O, S or agroup NR¹¹; R¹¹ and the groups R⁵ and R⁶ when attached to nitrogen atommay be the same or different and represent hydrogen, hydroxy, formyl orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino which may be mono ordialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, orsulfonic acid derivatives; n is an integer ranging from 1-4; Arrepresents an unsubstituted or substituted divalent aromatic orheterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, unsubstituted or substituted aralkyl group, orforms a bond with R⁸; R⁸ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, acyl group, unsubstituted or substituted aralkyl,or R⁸ forms a bond together with R⁷; R⁹ may be hydrogen or unsubstitutedor substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; the linking group represented by—(CH₂)_(n)—O—may be attached either through nitrogen atom or carbon atomand a process for its preparation and its use in the preparation ofβ-aryl-α-substituted hydroxy alklaoic acids is provided (Scheme-III)

The reaction of a compound of formula (IIIa) where all symbols are asdefined earlier with a compound of formula (IVi) where R⁹ is as definedearlier excluding hydrogen and Hal represent a halogen atom such as Cl,Br, or I may be carried out under conventional conditions in thepresence of a base. The base is not critical. Any base normally employedfor Wittig reaction may be employed metal hydride such as NaH or KH;metal alkoxides such as NaOMe or K^(t)BuO^(—) or NaOEt; or metal amidessuch as LiNH₂ or LiN(iPr)₂. Aprotic solvent such as THF, DMSO, dioxane,DME and the like may be used. Mixture of solvents may be used. HMPA maybe used as cosolvent. Inert atmosphere may be employed such as argon andhe reaction is more effective under anhydrous conditions. Temperature inthe range of −80° C. to 100° C. may be used. The compound of formula(IVj) where aHl symbols are as defined earlier may be onverted to acompound of formula (IVk) where R⁷ and R⁸ represent hydrogen atoms andall other symbols are as defined earlier, by treating with alcohol underanhydrous conditions in the presence of a strong anhydrous acid such asp-toluenesulfonic acid.

The compound of formula (IVk) defmed above upon. treatment withtrialkylsilyl cyanide such as trimethylsilyl cyanide produces a compoundof formula (IVf) where R⁷ and R⁸ represent hydrogen atoms and all othersymbols are as defined earlier.

In still another embodiment of the present invention there is providedthe novel intermediate of formula (IVg)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵and R⁶ when attached to carbon atom may be the same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl;unsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylaminowhich may be mono or dialkylamino group, arylamino, acylamino,aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonyl-amino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; W represents O, S or agroup NR¹¹; R¹¹ and the groups R⁵ and R⁶ when attached to nitrogen atommay be same or different and represent hydrogen, hydroxy, formyl orunsubstituted or substituted groups selected from all, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino which may be mono ordialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivatives, orsulfonic acid derivatives; n is an integer ranging from 1-4; Arrepresents an unsubstituted or substituted divalent aromatic orheterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or unsubstituted or substituted aralkyl group; R¹⁰may be hydrogen or unsubstituted or substituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orheteroaralkyl groups; the linking group represented by —(CH₂)_(n)—O—maybe attached either through nitrogen atom or carbon atom and a processfor its preparation and its use in the preparation ofβ-aryl-α-substituted hydroxyalkanoic acids is provided.

The compound of formula (IVg) where all other symbols are as definedearlier may be prepared by reacting a compound of formula (IVl)

where R⁸ is hydrogen atom and all other symbols are as defined earlier,with an appropriate diazotizing agent

The diazotization reaction may be under conventional conditions. Asuitable diazotizing agent is an alkyl nitrile, such as iso-amylnitrile. The reaction may be carried out in presence of solvents such asTHF, dioxane, ether, benzene and the like or a combination thereofTemperature in the range of −50° C. to 80° C. may be used. The reactionmay be carried out in an inert atmosphere which may be maintained byusing inert gases such as N₂, Ar or He. The duration of the reaction mayrange from 1 to 24 h, preferably, 1 to 12 h.

The compound of formula (IVl) may also be prepared by a reaction between(IIIe) where all symbols are as defined earlier and a compound offormula (IVm)

where R⁸ is hydrogen atom and all other symbols are as defined earlier.

The reaction of compound of formula (IIIe) where all symbols are asdefined earlier and a compound of formula (IVm) where all symbols are asdefmed earlier may be carried out in the presence of solvents such asTHF, DMF, DMSO, DME and the like or mixtures thereof The reaction may becarried out in an inert atmosphere which is maintained by using inertgases such as N₂, Ar or He. The reaction may be effected in the presenceof a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof Acetone maybe used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base. Thereaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours.

In yet another embodiment of the present invention there is provided thenovel termediates of formula (IIIm)

where, X represents O or S; the groups R¹, R², R³ and R⁴ may be same ordifferent and represent hydrogen, halogen, hydroxy, cyano, nitro,fonnyl;or unsubstituted or substituted groups selected from alkyl,cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy,heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy,acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino,alkylamino which may be mono or dialkylamino group, arylamino,acylamino, aralkylamino, aminoalkyl, hydroxy-alky, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; W represents O, S or agroup NR¹¹; R¹¹ represents hydrogen, hydroxy, fonnyl or unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl,heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino which may be mono ordialkylamino group, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalklyl, carboxylic acid derivatives, orsulfonic acid derivatives; n is an integer ranging from 1-4; Arrepresents an or unsubstituted or substituted divalent aromatic orheterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or unsubstituted or substituted aralkyl group orR⁷ forms a bond with R⁸; R⁸ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, acyl group, unsubstituted or substituted aralkyl,or R⁸ forms a bond together with R⁷; R⁹ may be hydrogen or unsubstitutedor substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminoccrbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; R¹⁰ may be hydrogen or unsubstituted orsubstituted groups selected from alky, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; the linking grouprepresented by —(CH₂)_(n)—O—may be attached either through nitrogen atomor carbcn atom and a process for its preparation and its use in thepreparation of β-aryl-α-oxysubstituted alkylcarboxylic acids isprovided.

The compound of formula (IIIm) where all symbols are as defined abovemay be prepared by reacting a compound of formula (IVn)

where all symbols are as defined earlier with a compound of formula(IVo) or (IVp)

The reaction of compound of formula (IVn) where all symbols are asdefined earlier with a compound of formula (IVo) or (IVp) where R¹, R²,R³, R⁴, W and X are as defined earlier to produce a compound of formula(IIIm) defined earlier may be carried out neat or in the presence ofsolvents such as xylene, toluene, dioxane, THF, DMF, DMSO, DME and thelike or their mixtures. The reaction may be carried out in an inertatmosphere which is maintained by using inert gases such as N₂, Ar orHe. The reaction temperature may range from 0° C.-150° C., preferably ata temperature in the range of 0° C.-120° C. The duration of the reactionmay range from 0.5 to 12 hours, preferably from 0.5 to 6 hours.

The compound of formula (IVn) and its preparation has been disclosed inour copending application 09/179,002 filed Oct. 26, 1998.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula (I) wherever applicable with 1 to 4 equivalents of abase such as sodium hydroxide, sodium methoxide, sodium hydride,potassium t-butoxide, potassium hydroxide, calcium hydroxide, magnesiumhydroxide and the like, in solvents like ether, THF, methanol,t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may beused. Organic bases like lysine, arginine, diethanolamine, choline,tromethamine, guanidine and their derivatives etc. may also be used.Alternatively, acid addition salts wherever applicable are prepared bytreatment with acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid,methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylicacid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinicacid, benzoic acid, benzenesulfonic acid, tartaric acid and the like insolvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc.Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR¹⁰represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with optically active amines, aminoacids, aminoalcoholsderived from aminoacids; conventional reaction conditions may beemployed to convert acid into an amide; the diastereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of compound of formula (I) may be prepared by hydrolyzingthe pure diastereomeric amide.

Various polymorphs of compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I) under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The compounds of general formula (I) are useful in the treatment and/orprophylaxis of insulin resistance (type II diabetes), leptin resistance,impaired glucose tolerance, dyslipidemia, disorders related to syndromeX such as hypertension, obesity, insulin resistance, coronary heartdisease, and other cardiovascular disorders. These compounds may also beuseful as aldose reductase inhibitors, for improving cognitive functionsin dementia, treating diabetic complications, disorders related toendothelial cell activation, psoriasis, polycystic ovarian syndrome(PCOS), inflammatory bowel diseases, osteoporosis and for the treatmentof cancer. The compounds of the present inventions are useful in thetreatment and/or prophylaxis of arteriosclerosis and/or xanthoma incombination with one or more HMG CoA reductase inhibitors,hypolipidemic/hypolipoproteinemic agents such as fibric acidderivatives, nicotinic acid, cholestyramnine, colestipol, or probucol.The compounds of the present invention in combination with HMG CoAreductase inhibitors, and/or hypolipidernic/hypolipoproteinemic agentscan be administered together or within such a period to actsynergistically. The HMG CoA reductase inhibitors may be selected fromthose used for the treatment or prevention of hyperlipidemia such aslovastatin, provastatin, simvastatiu, fluvastatin, atorvastatin,cerivastatin and their analogs thereof. Suitable fibric acid derivativemay be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrateand their analogs thereof.

The present invention also provides a pharmaceutical composition,containing the compounds of the general formula (I), as defined above,their tautomeric forms, their derivatives, their analogs, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates in combination withthe usual pharmaceutically employed carriers, diluents and the like.

The pharmaceutical composition may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like, may contain flavourants, sweeteners etc. in suitable solid orliquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. Such compositions typically containfrom 1 to 20%, preferably 1 to 10% by weight of active compound, theremainder of the composition being pharmaceutically acceptable carriers,diluents or solvents.

The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral or parenteralroutes. Administration by the oral route is preferred, being moreconvenient and avoiding the possible pain and irritation of injection.However, in circumstances where the patient cannot swallow themedication, or absorption following oral administration is impaired, asby disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 100 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

Suitable pharmaceutically acceptable carriers include solid fillers ordiluents and sterile aqueous or organic solutions. The active compoundwill be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral admninistration, the compounds can be combinedwith a suitable solid or liquid carrier or diluent to form capsules,tablets, powders, syrups, solutions, suspensions and the like. Thepharmaceutical compositions, may, if desired, contain additionalcomponents such as flavourants, sweeteners, excipients and the like. Forparenteral administration, the compounds can be combined with sterileaqueous or organic media to form injectable solutions or suspensions.For example, solutions in sesame or peanut oil, aqueous propylene glycoland the like can be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts or salts with base ofthe compounds. The injectable solutions prepared in this manner can thenbe administered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

The present invention is explained in detail in the examples given whichare provided by way of illustration only and therefore should not to beconstrued to limit the scope of the invention.

PREPARATION 1 Ethyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]-2-propenoate

To a stirred suspension of sodium hydride (756 mg, 32 mmol, 95%) in dryTHF (60 mL) was added a solution of ethyl(diethylphosphono)ethoxyacetate(6.20 g, 23.1 mmol) in THF (20 mL) at 0-5° C. dropwise and stirred for30 min at 5-25° C. To the reaction mixture was added a solution of4-[(2,2-diethoxy)ethoxy]benzaldehyde (5.0 g, 21.0 mmol) in THF (10 mL)at 25° C. and stirred further for 30 min. After completion of thereaction (TLC monitored), THF was removed and the resultant residue wasdiluted with water (100 mL) and extracted with ethyl acetate (3×25 mL).The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄ and concentrated to yield the title compound (6.5 g,88%) as a mixture of E/Z isomers.

¹H NMR (CDCl₃): δ 7.75 (d, J=8.77 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J=8.77Hz, 2H), 4.84 (t, J=5.12 Hz, 1H), 4.29 (q, J=7.10 Hz, 2H), 4.10-3.90 (m,4H), 3;90-3.55(m, 4H), 1.37 (t, J=7.10 Hz, 6H), 1.25 (t, J=7.03 Hz, 6H).

PREPARATION 2 Methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate

A mixture of ethyl 2-ethoxy3-[4-[(2,2-diethoxy)ethoxy]phenyl]-2-propenoate (500 mg, 1.42 mmol)obtained in preparation 1, and magnesium turnings (340 mg, 14.2 mmol) inmethanol (15 mL) was stirred at 45-50° C. until the reaction started (asevidenced by hydrogen evolution). On initiation of the reaction, themixture was stirred at 25° C. for a further 2 h. The reaction mixturewas added to ice water (15 mL), the pH adjusted to 7.5-8.0 using 10%aqueous hydrochloric acid, and the solution extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was chromatographedon silica gel using a gradient of 5-15% ethyl acetate in pet ether aseluent to afford the title compound (436 mg, 87%).

¹H NMR (CDCl₃): δ 7.14 (d, J=8.50 Hz, 2H), 6.84 (d, J=8.50 Hz, 2H), 4.82(t, J=5.15 Hz, 1), 4.05-3.92 (m, 1H), 3.97 (d, J=5.15 Hz, 2H), 3.85-3.50(m, 5H), 3;70 (s, 3H), 3.45-3.25 (m, 1H), 2.95 (d, J=6.64 Hz, 2H), 1.25(t, J=7.03 Hz, 6H), 1;16 (t, J=7.0 Hz, 3H).

PREPARATION 3 Ethyl2-phenoxy-3-[4-[(2,2-diethoxy)ethoy]phenyl]-2-propenoate

The title compound (2.25 g, 65%) as a mixture of E/Z isomers wasobtained from 4-[(2,2-diethoxy)ethoxy]benzaldehyde (2.05 g, 8.63 mmol),ethyl(diethylphosphono) phenoxy-acetate (3.0 g, 9.49 mmol) and NaH (310mg, 12.94 mmol, 95%) by a similar procedure to that described inpreparation 1.

¹H NMR (CDCl₃): δ 7.50-7.20 (m, 5H), 7.15-6.95 (m, 2H), 6.95-6.70 (m,3H), 4.90-4.70 (m, 1H), 4.30-4.08 (m, 2H), 4.03 (t, J=6.80 Hz, 2H),3.90-3;50 (m, 4H), 1.30-1.10 (m, 9H).

PREPARATION 4 Methyl2-phenoxy-3-[4-(2,2-diethoxy)ethoxy]phenyl]propanoate

The title compound (1.36 g, 66%) was obtained as a liquid from ethyl2-phenoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]-2-propenoate (2.05 g, 5.1mmol) obtained in preparation 3 and magnesium turnings (1.23 g, 51 mmol)by a similar procedure to that described in preparation 2.

¹H NMR (CDCl₃): δ 7.35-7.15 (m, 5H), 7.0-6.8 (m, 4H), 4.76 (t, J=5.20Hz, 1H), 3.98 (d, J=5.2 Hz, 2H), 3.8-3.5 (m, 5H), 3.71 (s, 3H), 3.18 (d,J=6.96 Hz, 2H), 1.24 (t, J=7.01 Hz, 6H).

EXAMPLE-1 Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-propenoate

The title compound (4.7 g, 76%) was obtained as a white solid from4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]benzaldehyde (4.5 g,15.15 mmol), ethyl(diethyl-phosphono)ethoxy acetate (4.9 g, 18.18 mmol)and NaH (545 mg, 22.73 mmol) by a similar procedure to that described inpreparation 1: mp 81-83° C.

¹H NMR (CDCl₃): δ 7.95 (d, J=6.64 Hz, 1H), 7.74 (d, J=8.72 Hz, 2H), 7.44(t, J=6.86 Hz, 1H), 7.20-7.00 (m, 2H), 7.02-6.80 (m, 3H), 5.37 (s, 2H),4.40-4.05 (m, 4H), 4.05-3.80 (m, 4H),1.50-1.20 (m, 6H).

EXAMPLE-2 (±)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

A solution of ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]-ethoxy]phenyl]-2-propenoate(4.5 g, 10.5 mmol) obtained in Example 1, in 1,4-dioxane (50 mnl) wasreduced with hydrogen in the presence of 10% palladium charcoal (450 mg)at 50-60 psi for 12 h. The reaction mixture was filtered through a bedof celite and the celite bed was washed with 1,4-dioxane. The filtratewas evaporated to dryness under reduced pressure to yield the titlecompound (3.5 g, 78%): mp 78-80° C.

¹H NMR (CDCl₃): δ 7.90 (d, J=7.56 Hz, 1H), 7.44 (t, J=7.05 Hz, 1H),7.26-7.07 (m, 3H), 6.97 (d, J=8.30 Hz, 1H), 6.80 (d, J=8.62 Hz, 2H),5.37 (s, 2H), 4.21-4.11 (m, 4H), 3.98-3.92 (m, 3H), 3.63-3.55 (m, 1H),3.37-3.29 (m, 1H), 2.93 (d, J=1.23 Hz, (t, J=7.10 Hz, 3H), 1.16 (t,J=7.05 Hz, 3H).

EXAMPLE-3(±)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid

To a stirred solution of ethyl2ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate(3.5 g, 8.5 mmol), obtained in Example 2, in methanol (25 mL) was addeda solution of sodium carbonate (4.5 g, 42.5 mmol) in water (25 mL) andstirred for 5 h at 25-30° C. Methanol was removed under reduced pressureand the aqueous layer was washed with ethylacetate. The aqueous layerwas acidified to pH 2.0 with 2N HCl. The white solid precipitated wasfiltered and dried to yield the title compound (3.04 g, 93%): mp103-105° C.

¹H NMR (CDCl₃): δ 8.05 (d, J=6.70 Hz, 1H), 7.54 (t, J=7.30 Hz, 1H), 7.25(d, J=8.20 Hz, 2H), 7.20 (t, J=7.30 Hz, 1H), 7.06 (d, J=8.20 Hz, 1H),6.90 (d, J=8.41 Hz, 2H), 5.46 (s, 2 H), 4.27 (t, J=4.70 Hz, 2H),4.11-3.90 (m, 1H), 4.05 (t, J=4.70 Hz, 2H), 3,80-3.60 (m, 1H), 3.60-3.40(m, 1H), 3.14 (dd, J=14.10 and 4.27 Hz, 1H), 3.04 (dd, J=14.20 and 7.50Hz, 1H), 1.26 (t, J=7.07 Hz, 3H).

EXAMPLE-4 (±)-Sodium2-ethoxy-3-[4-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

To a stirred suspension of(±)-2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid (100 mg, 0.26 mmol), obtained in Example 3 in methanol (3 mL) wasadded a solution of sodium methoxide (54 mg, 1.0 mmol) in methanol (1mL) dropwise at 30° C. The reaction mixture was stirred for further 1 h.Diethylether (5 mL) was added and the white solid precipitated wasfiltered and dried to afford the title compound (85 mg, 80%): mp186-188° C.

¹H NMR (CDCl₃): δ 7.83 (d, J=7.56 Hz, 1H), 7.56 (t, J=7.68 Hz, 1H),7.21-7.07 (m, 4H), 6.84 (d, J=8.39 Hz, 2H), 5.43 (s, 2 H), 4.13 (t,J=5.19 Hz, 2H), 3.87 (t, J=5.02 Hz, 2H), 3.62-3.48 (m, 2H), 3.12 (t,J=4.36 Hz, 1H), 2.86 (dd, J=14.12 and 3.32 Hz, 1H), 2.61 (dd, J=14.12and 9.04 Hz, 1H), 0.98 (t, J=7.01 Hz, 3H).

EXAMPLE-5 (+)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

To a stirred mixture of3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-1,3-benzoxazine (325 mg, 1.68 mmol)and triphenylphosphine (660 mg, 2.52 mmol) in toluene (10 mL) was addeda solution of (+)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (400 mg,1.68 mmol) at 25° C. and stirred for 10 min. To the reaction mixture wasadded diisopropyldiazodicarboxylate (0.5 mL, 2.52 mmol) at 25-30° C. andstirred for further 40 h. Water was added to the reaction mixture andextracted with ethyl acetate (3×10 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was chromatographed on silica gel using a gradient of 5-15%ethyl acetate in pet ether as eluent to afford the title compound (527mg, 76%): mp 76-78° C.

[α]_(D) ²⁵12.2 (C=0.5, MeOH);

¹H NMR (CDCl₃): δ 7.94 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.72 Hz, 1H),7.17-6.95 (m, 6H), 6.79 (d, J=8.30 Hz, 2H), 5.38 (s, 2H), 4.22-4.11 (m,3H), 3.95 (t, J=2H), 3.63-3.55 (m, 1H), 3.37-3.29 (m, 1H), 2.93 (d,J=6.64 Hz, 2H), 1.22 (t, J=7.06 Hz, 3H), 1.15 (t, J=7.05 Hz, 3H).

EXAMPLE-6 (−)-Ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yllethoxy]phenyl]propanoate

The title compound (500 mg, 64%) was obtained from3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-1,3-benzoxazine (364 mg, 1.89mmol), (−)-ethyl 2ethoxy-3-(4-hydroxyphenyl) propanoate (450 mg, 1.89mmol), triphenylphosphine (745 mg, 2.84 mmol) anddiisopropyl-diazodicarboxylate (575 mg, 2.84 mmol) by a similarprocedure to that described in Example 5: mp 76-78° C.

[α]_(D) ²⁵=−11.96 (C═0.51, MeOH);

¹H NMR (CDCl₃): δ 7.95 (d, J=7.75 Hz, 1H), 7.43 (t, J=7.45 Hz, 1H),7.22-7.03 (m, 3H), 6.97 (d, J=7.75 Hz, 1H), 6.79 (d, J=8.63 Hz, 2 H),5.37 (s, 2H), 4.22-4.05 (m, 4H), 4.05-3.86 (m, 3H), 3.70-3.50 (m, 1H),3.41-3.20 (m, 1H), 2.93 (d, 1.22 (t, J=7.05 Hz, 3H), 1.15 (t, J=7.05 Hz,3H).

EXAMPLE-7 [2R,N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(7a)

[2S,N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxyl]phenyl]-N-(2-hydroy-1-phenylethyl)propanamide(7b)

To a stirred solution of2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid (500 mg, 1.30 mmol) obtained in Example 3, in dry dichloromethane(6 mL) was added triethylamine (0.45 μL, 3.24 mmol) at 0° C., followedby addition of pivaloyl chloride (180 mg, 1.5 mmol) and stirred for 30min. at the same temperature. To this reaction mixture was added asolution of (S)(+)-2-phenylglycinol (180 mg, 1.3 mmol) indichloromethane (2 mL) containing triethylamine (0.37 mL, 2.6 mmol).After stirring for 1 h, dichloromethane (10 mL) was added and themixture was washed with water, brine, dried over anhydrous Na₂SO₄ andevaporated. The residue was chromatographed on silica gel using agradient of 10-50% ethyl acetate in pet ether as eluent to affordfirstly a diastereomer tentatively assigned as[2R,N(1S)]2-ethoxy-3-[4-[2-[4-oxo-3,4,-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(7a) followed by [2S, N(1S)]2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide (7b).

Spectral Data for 7a:

[α]_(D) ²⁵=43.8 (C=0.5, MeOH). mp: 64-68° C.;

¹H NMR (CDCl₃): δ 7.94 (d, J=7.80 Hz, 1H), 7.44 (t, J=7.38 Hz, 1H),7.40-7.26 (m, 3H), 7.26-7.10 (m, 4H), 7.10-6.95 (m, 2H), 6.82 (d, J=8.40Hz, 5.37 (s, 2H), 5.07-4.90 (m, 1H), 4.20 (t, J=4.63 Hz, 2H), 4.06-3.90(m, 3H), 3.69-3.65 (m, 2H), 3.48 (q, J=7.00 Hz, 2H), 3.11 (dd, J=14.10and 3.74 Hz, 1H), 2.92 (dd, J=14.10 and 6.23 Hz, 1H), 1.14 (t, J=7.00Hz, 3H).

Spectral data for 7b:

[α]_(D) ²⁵=5.20 (C=0.5, MeOH). mp: 88-92° C.;

¹H NMR (CDCl₃): δ 7.97 (d, J=7.75 Hz, 1H), 7.46 (t, J=7.75 Hz, 1H), 7.26(d, J=8.40 Hz, 1H), 7.30-6.95 (m, 7H), 6.73 (d, J=8.40 Hz, 2H), 5.40 (s,2H), 5.08-4.95 (m, 1H), 1H), 4.16 (t, J=4.70 Hz, 2H), 4.05-3.92 (m, 3H),3.90-3.82 (m, 2H), 3.54 (q, J=6,75 Hz, 2H), 3.10 (dd, J=14.10 and 3.74Hz, 1H), 2.90 (dd, J=14.10 and 6.73 Hz, 1H), 1,19 (t, J=7.01 Hz, 3H).

EXAMPLE-8(+)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid

Method A

A solution of [2R, N(1S)]2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide(1.60 g, 3.17 mmol) obtained in Example 7a, in a mixture of 1M sulphuricacid (40 mL) and dioxanewater (1:1, 144 mL) was heated at 100° C. for 16h. The reaction mixture was cooled to 25° C. and dioxane was removedunder reduced pressure. The remaining aqueous layer was extracted witethyl acetate (3×50 mL). The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated to yield the titlecompound (950 mg, 78%).

Method B

The title compound (116 mg, 83%) was obtained from (+)-ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate(150 mg, 0.36 mmol) obtained in Example 5, and sodium carbonate (192 mg,1.8 mmol) by a similar procedure to that described in Example 3: mp88-90° C.

[α]_(D) ²⁵=18.0 (C=0.5, MeOH);

¹H NMR (CDCl₃): δ 7.90 (d, J=7.66 Hz, 1H), 7.46 (t, J=7.60 Hz, 1H), 7.17(d, J=8.40 Hz, 2H), 7.12 (t, J=7.60 Hz, 1H), 6.98 (d, J=7.60 Hz, 1H),6.82 (d, J=8,40 Hz, 2H), 5.38 (s, 2H), 4.19 (t, J=4.70 Hz, 2H), 4.04(dd, J=7.35 and 4.35 Hz, 1H), 3.97 (t, J=4.70 Hz, 2H), 3.72-3.53 (m,1H), 3.53-3.38 (m, 1H), 3.12 (dd, J=14.11 and 4.35 Hz, 1H), 2.95 (dd,J=14.11 and 7.35 Hz, 1H), 1.17 (t, J=7.05 Hz, 3H).

EXAMPLE-9(−)-2-Ethoxy-3-[4-[2-[4oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid

Method A

The title compound (780 mg, 81%) was obtained from [2S, N(1S)]2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-N-(2-hydroxy-1-phenylethyl)propanamide (1.03 g, 2.5 mmol) obtained in Example 7b, by a similarprocedure described in Example 8 Method A.

Method B

The title compound (130 mg, 94%) was obtained from (−)-ethyl2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate(149 mg, 0.36 mmol) obtained in Example 6, and sodium carbonate (384 mg,1.8 mmol) by a similar procedure to that described in Example 3: mp91-93° C.

[α]_(D) ²⁵=−19.8 (C=0.5, MeOH);

¹H NMR (CDCl₃): δ 7.96 (d, J=7.80Hz, 1H), 7.46 (t, J=7.80 Hz, 1H), 7.16(d, J=8.45 Hz, 2H), 7.12 (t, J=7.40 Hz, 1H), 6.98 (d, J=7.40 Hz, 1H),6.82 (d, J=8.45 Hz, 2H),5.38 (s, 2H), 4.19 (t, J=4.75 Hz, 2H), 4.05 (dd,J=7.35 and 4.40 Hz, 1H), 3.96 (t, J=4.75 Hz, 2H), 3.70-3.50 (m, 1H),3.50-3.33 (m, 1H), 3.09 (dd, J=14.11 and 4.40 Hz, 1H), 2.95 (dd, J=14.11and 7.35 Hz, 1H), 1.18 (t, J=7.01 Hz, 3H).

EXAMPLE-10 (±)-Ethyl2-phenoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-propenoate

The title compound (520 mg, 56%) as a mixture of E/Z isomer was obtainedfrom 4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]benzaldehyde(594 mg, 2.0 mmol), ethyl(diethyl phosphono)phenoxyacetate (695 mg, 2.2mmol) (J. Org. Chem., 1983, 48, 3407) and sodium hydride(75 mg, 3.0mmol, 95%) as a base by a similar procedure to that described inpreparation 1: mp 104-106° C.

¹H NMR (CDCl₃): δ 8.05-7.90 (m, 1H), 7.67 (d, J=8.60 Hz, 1H), 7.60-7.20(m, 5H), 7.20-6.95 (m, 4H), 6.95-6.80 (m, 2H), 6.72 (s, 1H), 5.39 and5.35 (s, 2H), 4.40-4.08 (m, 4H), 4.08-3.90 (m, 2H), 1.20 and 1.07 (t,J=7.05 Hz, 3H).

EXAMPLE-11 (±)-Ethyl 2-ethoxy-3-[4-[2-[2, 2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

To a stirred solution of 2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazine(0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g,3.39 mmol) and stirred for 30 min. To this reaction mixture was added asolution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70g, 2.03 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585) in DMF (1mL) and stirred for 24 h at 60-70° C. The reaction mixturewas diluted with water and extracted with ethyl acetate (3×10 mL). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was chromatographed on silica gelusing a gradient of 5-15% of ethyl acetate in pet ether as eluent toafford the title compound (0.34 g, 45%) as a liquid.

¹HNMR (CDCl₃): δ 7.91 (d, J=7.50 Hz, 1H), 7.43 (t, J=7.50 Hz, 1H), 7.15(d, J=8.35 Hz, 2H), 7.06 (t, J=7.50 Hz, 1H), 6.89 (d, J=7.50 Hz, 1H),6.82 (d, J=8.35 Hz, 2), 4.28-4.05 (m, 4H), 4.05-3.80 (m, 3H), 3.70-3.50(m, 1H), 3.50-3.22 (m, 1H), 2.93 (d, J=6.65 Hz, 2H), 1.74 (s, 6H), 1.22(t, J=7.05 Hz, 3H); 1.15 (t, J=6.95 Hz, 3H).

EXAMPLE-12(±)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoic acid

The title compound (105 mg, 75%) was obtained from (±)-ethyl2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]pheny]propanoate(150 mg, 0.34 mmol) obtained in Example 11 and sodium carbonate (180 mg,1.7 mmol) by a similar procedure to that described in Example 3. mp:80-82° C.

¹H NMR (CDCl₃): δ 7.91 (d, J=7.50 Hz, 1H), 7.43 (t, J=7.50 Hz, 1H), 7.16(d, J=8.40 Hz, 2H), 7.06 (t, J=7.50 Hz, 1H), 6.88 (d, J=7.50 Hz, 1H),6.84 (d, J=8.40 Hz, 2H), 4.20 (t, J=5.30 Hz, 2H), 4.04 (dd, J=7.25 and4.25 Hz, 1H), 3.91 (t, J=5.30 Hz, 2H), 3.70-3.35 (m, 2H), 3.08 (dd,J=14.11 and 4.25 Hz, 1H), 2.93 (dd, J=14.11 and 7.25 Hz, 1H), 1.75 (s,6H), 1.17 (t, J=6.95 Hz, 3H).

EXAMPLE-13 (±) Methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate

To a stirred solution of polyphosphonate ethyl ester (PPE) (3.46 g, 8.0mmol) in chloroform (10 mL) was added salicylamide (548 mg, 4.0 mmol)followed by addition of a solution of (±)-Methyl2-ethoxy-3-[4-[(2,2diethoxy)ethoxy]phenyl]propanoate (1.28 g, 4.4 mmol)obtained in preparation 2, in chloroform (10 mL) dropwise at 25-30° C.The reaction mixture was immersed in a preheated oil bath at 70° C. andrefluxed 12 h. The reaction mixture was cooled to room temperature andCHCl₃ was removed under reduced pressure. The resultant residue wasneutralised (pH=7.0) with saturated aqueous NaHCO₃ solution andextracted with ethyl acetate (3×20 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated.The crude compound was chromatographed on silica gel using a gradient of5-25% of ethyl acetate in pet ether as eluent to afford the titlecompound (1.15 g, 72%) as a pale yellow liquid.

¹H NMR (CDCl₃): δ 7.97 (d, J=7.75 Hz, 1H), 7.50 (t, J=8.50 Hz, 1H), 7.19(d, J=8.62 Hz, 2H), 7.15 (t, J=7.50 Hz, 1H), 7.02 (d, J=8.50 Hz, 1H),6.87 (d, J=8.62 Hz, 2H), 5.69 (t, J=4.95 Hz, 1H), 4.39 (dd, J=9.64, 4.19Hz, 1H), 4.30-3.90 (m, 2H), 3.72 (s, 3H), 3.71-3.50 (m, 1H), 3.45-3.21(m, 1H), 2.97 (d, J=6.96 Hz, 2H), 1.17 (t, J=7.05 Hz, 3H).

EXAMPLE-14 (±)-2-Ethoxy-3-4-[[4-oxo-3,4-dihydro1,3-benzoxazin-2-yl]methoxy]phenyl]propanoico acid

The title compound (300 mg, 75/o) was obtained from (±)-methyl2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]ethoxy]phenyl]propanoate(432 mg, 1.08 mmol) obtained in Example 13, and sodium carbonate (318mg, 3.0 mmol) by a similar procedure to that described in Example 3. mp:126-128° C.

¹H NMR (CDCl₃): δ 7.96 (d, J=7.80 Hz, 1H), 7.50 (t, J=7.80 Hz, 1H), 7.19(d, J=8.50 Hz, 2H), 7.12 (t, J=7.80 Hz, 1H), 7.01 (d, J=7.80 Hz, 1H),6.84 (d, J=8.50 Hz, 2H), 5.65 (t, J=5.35 Hz, 1H), 4.35 (dd, J=9.90 and4.25 Hz, 1H), 4.16 (dd, J=9.60 and 6.60 Hz, 1H), 4.07 (t, J=5.80 Hz,1H), 3.70-3.52 (m, 1H), 3.52-3.40 (m, 1H), 3.20-2.90 (m, 2H), 1.20 (t,J=7.05 Hz, 3H).

EXAMPLE-15 (±)-Methyl2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2quinazolinyl]methoxy]phenyl]propanoate

The title compound (900 mg, 62%) was obtained as a liquid fromanthranilamide (500 mg, 3.67 mmol), (±)-methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.43 g, 4.0 mmol)obtained in preparation 2 and polyphosphonate ethyl ester (3.18 g, 7.35mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl₃): δ 7.91 (d, J=7.50 Hz, 1H), 7.36 (t, J=7.50 Hz, 1H), 7.19(d, J=8.40 Hz, 2H), 6.90 (t, J=7.50 Hz, 1H), 6.85 (d, J=8.40 Hz, 2H),6.72 (d, J=7.50 Hz, 1H), 6.37 (bs, 1H, D₂O exchangeable), 5.23 (t,J=5.00 Hz, 1H), 4.40-4.10 (m, 2H), 4.10-3.90 (m, 1H), 3.74 (s, 3H),3.70-3.52 (m, 1H), 3.48-3.22 (m, 1H), 2.99 (d, J=6.22 Hz, 2H), 1.19 (t,J=6.95 Hz, 3H).

EXAMPLE-16(±)-2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid

The title compound (360 mg, 69%) was obtained from (±)-methyl2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate(560 mg, 1.4 mmol) obtained in Example 15, and sodium carbonate (750 mg,7.0 mmol) by a similar procedure to that described in Example 3: mp 173°C.

¹H NMR (CDCl₃+DMSO): δ 7.79 (d, J=7.50 Hz, 1H), 7.44 (bs, 1H, D₂Oexchangeable), 7.27 (t, J=7.50 Hz, 1H), 7.17 (d, J=8.30 Hz, 2H),6.81-6.69 (m, 4H), 5.87 (bs, 1H, D₂O exchangeable ), 5.12 (t, J=5.10 Hz,1H), 4.20-3.95 (m, 2H), 3.92 (dd, J=7.80, 4.89 Hz, 1H), 3.72-3.50 (m,1H), 3.40-3.20 (m, 1H), 3.10-2.80 (m, 2H), 1.14 (t, J=6.95 Hz, 3H).

EXAMPLE-17 (±)-Methyl-2-ethoy-3-[4-[[6-chloro-4-oxo-, 1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate

The title compound (640 mg, 50%) was obtained as a liquid from5-chloroanthranilamide (500 mg, 2.93 nmmol), (±)-methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.41 g, 3.22mmol) obtained in preparation 2 and polyphosphonate ethyl ester (2.53 g,5.86 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl₃): δ 7.83 (d, J=2.26 Hz, 1H), 7.23 (t, J=8.60 Hz, 1H), 7.13(d, J=8.40 Hz, 2H), 6.78 (d, J=8.40 Hz, 2H), 6.63 (d, J=8.60 Hz, 1H),5.17 (t, J=4.70 Hz, 1H), 4.75 (bs, 1H, D₂O exchangeable), 4.11 (t,J=6.60, 1H), 3.99 (q, J=4.70 Hz, 2H), 3.70 (s, 3H), 3.70-3.50 (m, 1H),3.40-3.20 (m, 1H), 2.95 (d, J=6.60 Hz, 2H), 1.14 (t, J=6.95 Hz, 3H).

EXAMPLE-18(±)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid

The title compound (140 mg, 73%) was obtained from (±)-methyl2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate(200 mg, 0.46 mmol) obtained in Example 17 and sodium carbonate (245 mg,2.31 mmol) by a similar procedure to that described in Example 3: mp:156-158° C.

¹H NMR (CDCl3): δ 8.19 (s, 1H), 7.25-7.05 (m, 1H), 7.13 (d, J=8.30 Hz,2H), 7.03 (bs, 1H, D₂O exchangeable), 6.85-6.70 (m, 1H), 6.78 (d, J=8.30Hz, 2H), 5.02 (t, J=4.90 Hz, 1H), 4.10-3.80 (m, 3H), 3.70-3.45 (m, 1H),3.45-3.20 (m, 1H), 3.0-2.70 (m, 2H), 1.08 (t, J=6.95 Hz, 3H).

EXAMPLE-19 (±)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxyl]phenyl]propanoate

The title compound (870 mg, 41%) was obtained as a liquid from N-methylanthranilamide (765 mg, 5.1 mmol), (±)-methyl2ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate obtained inpreparation 2 (2.0 g, 5.6 mmol) and polyphosphonate ethyl ester (4.40 g,10.2 mmol) by a similar procedure to that described in Example 13: mp138-140° C.

¹H NMR (CDCl₃): δ 7.91 (d, J=7.60 Hz, 1H), 7.27 (t, J=7.60 Hz, 1H), 7.13(d, J=8.50 Hz, 2H), 6.86 (t, J=7.60 Hz, 1H), 6.75 (d, J=8.50 Hz, 2H),6.65 (d, J=7.60 Hz, 1H), 4.94 (dd, J=8.50 and 3.25 Hz, 1H), 4.82 (bs,1H, D₂O exchangeable), 4.11 (t, J=8.80 Hz, 1H), 4.02-3.90 (m, 2H), 3.70(s, 3H), 3.70-3.48 (m, 1H), 3.42-3.25 (m, 1H), 3,20 (s, 3H), 2.94 (d,J=6.13 Hz, 2H), 1.15 (t, J=7.01 Hz, 3H1).

EXAMPLE-20(±)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid

The title compound (64 mg, 72%) was obtained as a liquid from (±)-methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetahydro-2-quinazolinyl]methoxy]phenyl]propanoateobtained in Example 19 (100 mg, 0.23 mmol) and sodium carbonate (124 mg,1.16 mmol) by a similar procedure to that described in Example 3:

¹H NMR (CDCl₃): δ 7.90 (d, J=7.50 Hz, 1H), 7.26 (t, J=7.50 Hz, 1H), 7.14(d J=8.40 Hz, 2H), 6.86 (t, J=7.50 Hz, 1H), 6.75 (d, J=8.40 Hz, 2H),6.65 (d, J=7.50 Hz, 1H), 4.95 (dd, J=8.65 and 3.85 Hz, 1H), 4.20-3.90(m, 3H), 3.75-3.35 (m, 2H), 3.20 (s, 3H, 3.15-2.80 (m, 2H), 1.18 (t,J=7.0 Hz, 3H).

EXAMPLE-21 (±)-Methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2yl]methoxy]phenyl]propanoate

The title compound (735 mg, 60%) was obtained as a gummy mass fromN-methyl salicylamide (450 mg, 3.0 mmol), (±)-methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate obtained inpreparation 2 (1.16 g, 3.3 mmol) and polyphosphonate ethyl ester (2.59g, 6.0 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl3): δ 7.93 (d, J=7.50 Hz, 1H), 7.42 (t, J=7.50 Hz, 1H), 7.12(d, J=8.40 Hz, 2H), 7.09 (t, J=7.50 Hz, 1H), 6.94 (d, J=7.50 Hz, 1H),6.75 (d, J=8.40 Hz, 2H), 5.62 (t, J=5.50 Hz, 1H), 4.25 (dd, J=10.25 and6.25 Hz, 1H), 4.12 (dd, J=10.25 and 5.25 Hz, 1H), 3.96 (t, J=6.50 Hz,1H), 3.70 (s, 3H), 3.70-3.50 (m, 1H), 3.40-3.15 (m, 1H), 3.22 (s, 3H),2.93 (d, J=6.50 Hz, 2H), 1.14 (t, J=7.05 Hz, 3H).

EXAMPLE-22(±)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoicacid

The title compound (325 mg, 75%) was obtained as a liquid from(±)-methyl2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propanoate(472 mg, 1.18 mmol) obtained in Example 21 and sodium carbonate (362 mg,3.42 mmol) by a similar procedure to that described in Example 3.

¹H NMR (CDCl₃): δ 7.90 (d, J=7.50 Hz, 1H), 7.40 (t, J=7.50 Hz, 1H), 7.10(d, J=8.40 Hz, 2H), 7.05 (t, J=7.50 Hz, 1H), 6.90 (d, J=7.50 Hz, 1H),6.75 (d, J=8.40 Hz, 2H), 5.30 (t, J=5.50 Hz, 1H), 4.20 (dd, J=9.75, 5.95Hz, 1H), 4.10 (dd, J=9.75 and 4.95 Hz, 1H), 4.01 (t, J=6.40 Hz, 1H),3.72-3.52 (m, 1H), 3.42-3.20 (m, 1H), 3.20 (s, 3H), 3.05-2.80 (m, 2H,),1.15 (t, J=6.95 Hz, 3H).

EXAMPLE-23 (±)-Methyl2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate

The title compound (1.18 g, 54%) was obtained as a colorless liquid fromN-ethyl-anthranilamide (840 mg, 5.1 mmol), (±)-methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate obtained inpreparation 2 (2.0 g, 5.6 mmol) and polyphosphonate ethyl ester (4.40 g,10.2 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl3): δ 7.89 (d, J=7.50 Hz, 1H), 7.25 (t, J=7.50 Hz, 1H), 7.11(d, J=8.40 Hz, 2H), 6.83 (t, J=7.50 Hz, 1H), 6.73 (d, J=8.40 Hz, 2H),6.63 (d, J=7.50 Hz, 1H), 4.95 (dd, J=8.72 and 3.32 Hz, 1H), 4.40-3.80(m, 4H), 3.68 (s, 3H), 3.62-3.40 (m, 1H), 3.40-3.22 (m, 1H), 3.22-3.02(m, 1H), 2.93 (d, J=6.22 Hz, 2H), 1.28 (t, J=7.15 Hz, 3H), 1.14 (t,J=6.95 Hz, 3H).

EXAMPLE-24(±)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid

The title compound (324 mg, 81%) was obtained as a liquid from(±)-methyl2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolnyl]methoxy]phenyl]propanoateobtained in Example 23 (520 mg, 1.22 mmol) and sodium carbonate (647 mg,6.1 mmol) by a similar procedure to that described in Example 3.

¹H NMR (CDCl₃): δ 7.85 (d, J=7.50 Hz, 1H), 7.20 (t, J=7.50 Hz, 1H), 7.10(d, J=8.40 Hz, 2H), 6.80 (t, J=7.50 Hz, 1H), 6.70 (d, J=8.40 Hz, 2H),6.60 (d, J=7.40 Hz, 1H), 4.90 (dd, J=8.50 and 3.25 Hz, 1H), 4.40-3.80(m, 4H), 3.70-3.40 (m, 1H), 3.40-3.20 (m, 3.20-3.00 (m, 1H), 2.90 (d,J=6.20 Hz, 2H), 1.25 (t, J=7.10 Hz, 3H), 1.14 (t, J=7.00 Hz, 3H).

EXAMPLE-25 (±)-Methyl2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoiy]phenyl]propanoate

The title compound (400 mg, 54%) was obtained as a liquid fromN,N¹-dimethyl-anthranilamide (295 mg, 1.79 mmol), (±)-methyl2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (700 mg, 1.97mmol), obtained in preparation 2 and polyphosphonate ethylester (1.54 g,3.58 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl₃): δ 7.92 (d, J=7.50 Hz, 11), 7.35 (t, J=8.30 Hz, 1H), 7.08(d, J=8.40 Hz, 2H), 6.82 (t, J=7.50 Hz, 1H), 6.67 (d, J=8.40 Hz, 2H),6.61 (d, J=8.32 Hz, 1H), 4.85 (d, J=5.80 Hz, 1H), 4.29-3.90 (m, 3H),3.70-3.50 (m, 1H), 3.67 (s, 3H), 3.40-3.20 (m, 1H), 3.22 (s, 3H), 3.10(s, 3H), 2.90 (d, J=6.55 Hz, 2H), 1.12 (t, J=6. 97 Hz, 3H).

EXAMPLE-26(±)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxyl]phenyl]propanoicacid

The title compound (103 mg, 72%) was obtained as a liquid from(±)-methyl2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate(150 mg, 0.36 mmol), obtained in Example 25 and sodium carbonate (192mg, 1.81 mmol) by a similar procedure to that described in Example 3.

¹H NMR (CDCl₃): δ 7.90 (d, J=7.50 Hz, 1H), 7.30 (t, J=8.30 Hz, 1H), 7.05(d, J=8.40 Hz, 2H), 6.80 (t, J=7.50 Hz, 1H), 6.60 (d, J=8.40 Hz, 2H),6.60 (d, J=8.30 Hz, 1H), 4.80 (t, J=5.80 Hz, 1H), 4.30-3.90 (m, 3H),3.70-3.50 (m, 1H), 3.40-3.20 (m, 1H), 3.20 (s, 3H), 3.10 (s, 3H,), 2.90(d, J=6.50 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H).

EXAMPLE-27 (±)-Methyl2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate

The title compound (395 mg, 58%) was obtained as a liquid fromanthranilamide (200 mg, 1.47 mmol), (±)-methyl2-phenoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (650 mg, 1.61mmol) obtained in preparation 4 and polyphosphonate ethyl ester (1.27 g,2.94 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl₃): δ 7.90 (d, J=7.75 Hz, 1H), 7.34 (t, J=7.75 Hz, 1H),7.35-7.15 (m, 3H), 7.23 (d, J=8.40 Hz, 2H), 6.96 (t, J=7.80 Hz, 1H),6.90-6.80 (m, 2H), 6.83 (d, J=8.40 Hz, 2H), 6.69 (d, J=7.80 Hz, 1H),6.55 (bs, 1H, D₂O exchangeable), 5.20 (t, J=6.50 Hz, 4.76 (t, J=6.40 Hz,1H), 4.65 (bs, 1H, D₂O exchangeable), 4.20 (dd, J=8.90 and 7.15 Hz, 1H),4.01 (dd, J=8.90 and 5.15 Hz, 1H), 3.72 (s, 3H), 3.19 (d, J=6.40 Hz,2H).

EXAMPLE-28(±)-2-Phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoic acid

The title compound (488 mg, 86%) was obtained as a white solid from(±)-methyl2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate(611 mg, 1.14 mmol) obtained in Example 27 and sodium carbonate (726 mg,6.84 mmol) by a similar procedure to that described in Example 3, m.p:78-80° C.

¹H NMR (CDCl₃): δ 7.94 (bs, 1H, D₂O exchangeable), 7.83 (d, J=7.38 Hz,1H), 7.40-7.15 (m, 5H), 6.98 (t, J=7.38 Hz, 1H), 6.92 (d, J=8.30 Hz,2H), 6.84 (t, J=8.40 Hz, 1H), 6.72 (d, J=8.30 Hz, 2H), 6.63 (d, J=8.40Hz, 1H), 4.98 (t, J=5.10 Hz, 1H), 4.89 (t, J=5.30 Hz, 1H), 3.94 (dd,J=8.90 and 7.15 Hz, 1H), 3.70 (dd, J=8.90 and 4.05 Hz, 1H), (d, J=5.30Hz, 2H).

EXAMPLE-29 (±)-Methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate

The title compound (488 mg, 47%) was obtained as a liquid from5-chloroanthranilamide (368 mg, 2.15 mmol), (±)-methyl2-phenoxy-3-[4-[(2,2-diethoxy) ethoxy]phenyl]propanoate (954 mg, 2.37mmol) obtained in preparation 4 and polyphosphonate ethyl ether (1.864mg, 4.3 mmol) by a similar procedure to that described in Example 13.

¹H NMR (CDCl₃): δ 7.84 (s, 1H), 7.31-7.19 (m, 5H), 7.01-6.91 (m, 1H),6.85-6.79 (m, 4H), 6.61 (d, J=8.62 Hz, 1H), 5.16 (bs, 11H), 4.75 (t,J=6.22 Hz, 2H), 4.19-4.06 (m, 1H), 3.71 (s, 3H), 3.18 (d, J=6.55 Hz,2H).

EXAMPLE-30(±)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoicacid

The title compound (300 mg, 65%) was obtained from (±) methyl2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]propanoate(488 mg, 1.01 mmol) obtained in Example 29 and sodium carbonate (530 mg,5.08 mmol) by a similar procedure to that described in Example 3: mp:54-56° C.

¹H NMR (CDCl₃): δ 7.80 (s, 1H), 7.31-7.18 (m, 5H), 6.99 (d, J=7.47 Hz,1H), 6.90 (d, J=8.3 Hz, 2H), 6.73 (d, J=8.54 Hz, 2H), 6.58 (d, J=7.88Hz, 1H), 5.02 (bs, 1H), 4.89 (t, J=4.98 Hz, 1H), 4.01-3.91 (m, 1H),3.78-3.66 (m, 1H), 3.25 (d, J=5.30 Hz, 2H).

EXAMPLE-31 (±)-Ethyl2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

The title compound (160 mg, 41.5%) was obtained as a liquid from3-(2-hydroxyethyl)-6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazine (200 mg,0.84 mmol), (±)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (200 mg,0.84 mmol), triphenylphosphine (330 mg, 1.26 mol) anddiisopropyldiazodicarboxylate (255 mg, 1.26 mmol) by a similar procedureto that described in Example 5.

¹H NMR (CDCl₃): δ 8.82 (s, 1H), 8.35-8.26 (m, 11H), 7.19-7.04 (m, 3H),6.77 (d, J=8.54 Hz, 2H), 5.47 (s, 2H), 4.28-4.10 (m, 5H), 3.96 (t,J=4.77 Hz, 2H), 3.68-3.50 (m, 1H), 3.40-3.22 (m, 1H), 2.92 (d, J=6.55Hz, 2H), 1.35-1.09 (m, 6H).

EXAMPLE-32(±)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]pheyl]propanoicacid

The title compound (226 mg, 63%) was obtained from (±)thyl2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate(339 mg, 0.74 mmol) obtained in Example 31 and sodium carbonate (392 mg,3.70 mmol) by a similar procedure to that described in Example 3: mp:110° C.

¹H NMR (CDCl₃): δ 8.87 (s, 1H), 8.40-8.31 (m, 1H), 7.31-7.10 (m, 3H),6.81 (d, J=8.40 Hz, 2H), 5.50 (s, 2H), 4.21 (t, J=4.56 Hz, 2H),4.11-3.98 (m, 3H), 3.70-3.39 (m, 2H), 3.16-2.90 (m, 2H), 1.19 (t, J=6.98Hz, 3H).

EXAMPLE-33 (±)-Ethyl2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate

The title compound (168 mg, 43.4%) was obtained as a liquid from3-(2-hydroxy-ethyl)-6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazine (200 mg,0.85 mmol), (±)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (202 mg,0.85 mmol), triphenylphosphine (334 mg, 1.27 mmol) anddiisopropyldiazodicarboxylate (258 mg, 1.27 mmol) by a similar procedureto that described in Example 5.

¹H NMR (CDCl₃): δ 8.51 (s, 1H), 8.08 (d, J=6.41 Hz, 1H), 7.13 (d, J=8.63Hz, 2H), 7.02 (d, J=8.72 Hz, 1H), 6.77 (d, J=8.63 Hz, 2H), 5.41 (s, 2H),4.28-4.08 (m, 5H), 3.93 (t, J=4.86 Hz, 2H), 3.65-3.49 (m, 1H), 3.41-3.21(m, 1H), 2.92 (d, J=6.64 Hz, 2H), 2.59 (s, 3H), 1.39-1.10 (m, 6H).

EXAMPLE-34(±)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoicacid

The title compound (120 mg, 84%) was obtained as a liquid from (±)-ethyl2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoate(152 mg, 0.33 mmol) obtained in Example 33 and sodium carbonate (177 mg,1.67 mmol) by a similar procedure to that described in Example 3.

¹H NMR (CDC₁₃): δ 8.53 (s, 1H), 8.11 (d, J=6.50 Hz, 1H), 7.16 (d, J=8.40Hz, 2H), 7.04 (d, J=8.72 Hz, 1H), 6.80 (d, J=8.40 Hz, 2H), 5.40 (s, 2H),4.16 (t, J=2H), 3.91-4.04 (m, 3H), 3.70-3.51 (m, 1), 3.50-3.31 (m, 1H),3.12-2,88 (m, 2H), 2,61 (s, 3H), 1.16 (t, J=6.84 Hz, 3H).

The compounds of the present invention lowered random blood sugar level,triglyceride, total cholesterol, LDL, VLDL and increased HDL. This wasdemonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds

A) In vitro

a) Determination of hPPARα activity

Ligand binding domain of hPPARα was fused to DNA binding domain of Yeasttranscription factor GAL4 in eucaryotic expression vector. Usingsuperfect (Qiagen, Germany) as transfecting reagent HEK-293 cells weretransfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARα was measured using Packard Luclitekit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene. 1992. 118: 137-141; Superfect TrnsfectionReagent Handbook. February, 1997. Qiagen, Germany).

b) Determination of hPPARγ activity

Ligand binding domain of hPPARγ1 was fused to DNA binding domain ofYeast transcription factor GAL4 in eucaryotic expression vector. Usinglipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat 1 μM concentration after 48 hrs of transfection and incubatedovernight. Luciferase activity as a function of drug binding/activationcapacity of PPARγ1 was measured using Packard Luclite kit (Packard, USA)in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag andMelvyn Hollis. Gene. 1992. 118:137-141; Guide to EukaryoticTransfections with Cationic Lipid Reagents. Life Technologies, GIBCOBRL, USA).

Example No Concentration PPARα Concentration PPARγ Example 3 50 μM 7 1μM 11

c) Determination of HMG CoA reductase inhibition activity

Liver microsome bound reductase was prepared from 2% cholestramine fedrats at mid-dark cycle. Spectrophotometric assays were carried out in100 mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg ofliver microsomal enzyme. Total reaction mixture volume was kept as 1 ml.Reaction was started by addition of HMG CoA. Reaction mxue was incubatedat 37° C. for 30 min and decrease in absorbance at 340 nm was recorded.Reaction mixture without substrate was used as blank (Goldstein, J. Land Brown, M. S. Progress in understanding the LDL receptor and HMG CoAreductase, two membrane proteins that regulate the plasma cholesterol.J. Lipid Res. 1984, 25: 1450-1461). The test compounds inhibited the HMGCoA reductase enzyme.

B) In vivo

a) Efficacy in genetic models

Mutation in colonies of laboratory animals and different sensitivitiesto dietary. regimens have made the development of animal models withnon-insulin dependent diabetes and hyperlipidemia associated withobesity and insulin resistance possible. Genetic models such as db/dband ob/ob (Diabetes, (1982) 31 (1):1-6) mice and zucker fa/fa rats havebeen developed by the various laboratories for understanding thepathophysiology of disease and testing the efficacy of new antidiabeticcompounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab.(1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db micedeveloped by Jackson Laboratory, US, are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight rangeof 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animalhouse, were used in the experiment The mice were provided with standardfeed (National Institute of Nutrition (NIN), Hyderabad, India) andacidified water, ad libitum. The animals having more than 350 mg/dlblood sugar were used for testing. The number of animals in each groupwas 4.

Test compounds were suspended on 0.25% carboxymethyl cellulose andadministered to test group at a dose of 0.001 mg to 30 mg/kg throughoral gavage daily for 6 days. The control group received vehicle (dose10 ml/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO4oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula described below.

No adverse effects were observed for any of the mentioned compounds ofinvention in the above test.

Reduction in Blood Triglyceride Compound Dose (mg/kg) Glucose Level (%)Lowering (%) Example 14 3 55 46 Example 16 3 18 13 Example 19 3 31 62

The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Demarkand were used at 8 weeks of age. Zucker fafa fatty rats were obtainedfrom IffaCredo, France at 10 weeks of age and were used at 13 weeks ofage. The animals were maintained under 12 hour light and dark cycle at25±1° C. Animals were given standard laboratory chow (NIN, Hyderabad,India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T.,Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabeticagent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats.Diabetes. 1988. 37: 1549-1558).

The test compounds were administered at 0.1 to 30 mg/kg/day dose for 9days. The control animals received the vehicle (0.25%carboxymethylcellulose, dose 10 ml/kg) through oral gavage.

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centfugation, plasma sample was separated for triglyceride,glucose, free fatty acid, total cholesterol and insulin estimations.Measurement of plasma triglyceride, glucose, total cholesterol were doneusing commercial kits (Dr. Reddy's Laboratory, Diagnostic Division,Hyderabad, India). The plasma free fatty acid was measured using acommercial kit form Boehringer Mannheim, Germany. The plasma insulin wasmeasured using a RIA kit (BARC, India). The reduction of variousparameters examined are calculated according to the formula.

In ob/ob mice oral glucose tolerance test was performed after 9 daystreatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg ofglucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

The experimental results from the db/db mice, ob/ob mice, Zucker fa/farats suggest that the novel compounds of the present invention alsopossess therapeutic utility as a prophylactic or regular treatment fordiabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

Blood glucose level and triglycerides are also lowered at doses greaterthan 10 mg/kg. Normally, the quantum of reduction is dose dependent andplateaus at certain dose.

b) Cholesterol lowering activity in hypercholesterolemic rat models:

Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.Animals were maintained under 12 hour light and dark cycle at 25±1° C.Rats of 180-200 gram body weight range were used for the experimentAnimals were made hypercholesterolemic by feeding 2% cholesterol and 1%sodium cholate mixed with standard laboratory chow [National Instituteof Nutrition (NIN), Hyderabad, India] for 6 days. Throughout theexperimental period the animals were maintained on the same diet (Petit,D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate onliver lipids and lipoprotein synthesis in normo- and hyperlipidemicrats. Atherosclerosis. 1988. 74: 215-225).

The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement 2of plasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula.

Tri- Total Com- Dose glyceride Cholesterol HDL↑ LDL↓ VLDL↓ pound Mg/kg(%)↓ (%)↓ (%) (%) (%) Ex- 3 61 64 256 76 67 ample 4 mg/kg Ex- 0.3 62 64110 74 50 ample 3 mg/kg

c) Plasma triglyceride and total cholesterol lowering activity in Swissalbino mice and Guinea Digs

Male Swiss albino mice (SAM) and male Guinea pigs were obtained from NINand housed in DRF animal house. All these animals were maintained under12 hour light and dark cycle at 25±1° C. Animals were given standardlaboratory chow (NIN, Hyderabad, India) and water, ad libitum. SAM of20-25 g body weight range and Guinea pigs of 500-700g body weight rangewere used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V.,Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil andnicotinic acid on plasma lipoprotein levels in normal and hyperlipidemicmice. Atherosclerosis. 1988. 70: 107-114).

The test compounds were administered orally to Swiss albino mice at 0.3to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle(0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds wereadministered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifigation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergermeyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann Clin.Biochem. 1969. 6: 24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (D)r. Reddy'sDiagnostic Division, Hyderabad, India).

Compound Dose (mg/kg) Triglyceride (%)↓ Example 7 3 61 Example 18 3 63Example 19 3 51

Formulae for calculation:

1. Percent reduction in Blood sugar/triglycerides/total cholesterol werecalculated according to the formula:${{Percentage}\quad {reduction}\quad (\%)} = {\lbrack {1 - \frac{{TT}/{OT}}{{TC}/{OC}}} \rbrack \times 100}$OC = Zero  day  control  group  valueOT = Zero  day  treated  group    valueTC = Test    day  control  group  valueTT = Test  day  treated  group  value

2. LDL and VLDL cholesterol levels were calculated according to theformula:${{LDL}\quad \text{cholesterol in mg/dl}} = \quad {\lbrack {\text{Total cholesterol} - {{HDL}\quad \text{cholesterol}} - \frac{\text{triglyceride}}{5}} \rbrack \text{mg/dl}}$

VLDL cholesterol in mg/dl=[Total cholesterol−HDL cholesterol−LDLcholesterol] mg/dl

What is claimed is:
 1. An intermediate of formula (IIIm)

where, X represents O or S; the groups R¹, R², R³ and R⁴ may be same ordifferent and represent hydrogen, halogen, hydroxy, cyano, nitro,formyl; or unsubstituted or substituted groups selected from alkyl,cycloalkyl, alkoxy, cycloalkyloxy, aryl, aryloxy, aralkyl, aralkoxy,heterocyclyl, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy,acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino,alkylamino which may be mono or dialkylamino group, arylamino,acylamino, aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsamides, or sulfonic acid or its amides; W represents O; n is an integerranging from 1-4; Ar represents an unsubstituted or substituted divalentaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkylgroup or forms a bond with R⁸; R⁸ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substitutedaralkyl, or R⁸ forms a bond together with R⁷; R⁹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ representshydrogen or unsubstituted or substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkylgroups; and the linking group represented by —(CH₂)_(n)—O—may beattached either through nitrogen atom or carbon atom.
 2. A process forthe preparation of compound of formula (IIIm) as defined in claim 1,which comprises reacting a compound of formula (IVn)

where all symbols are as defined earlier with a compound of formula(IVo) or (IVp)

where all symbols are as defined earlier.
 3. An intermediate of formula(IVf)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵and R⁶ when attached to carbon atom may be the same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl; orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylaminowhich may be mono or dialkylamino group, arylamino, acylamino,aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsamides, or sulfonic acid or its amides; W represents O; n is an integerranging from 1-4; Ar represents an unsubstituted or substituted divalentaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkylgroup or forms a bond with R⁸; R⁸ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, acyl group or unsubstituted or substitutedaralkyl or R⁸ forms a bond together with R⁷; R⁹ represents hydrogen orunsubstituted or substituted groups selected from alkyl, cycloalkyl,aryl, aralkyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; and the linking grouprepresented by —(CH₂)_(n)—O—may be attached either through nitrogen atomor carbon atom.
 4. A process for the preparation of compound of formula(IVf) defined above, where R⁷ and R⁸ represent hydrogen atoms and allother symbols are as defined above which comprises: a) reacting acompound of formula (IIIa)

 where all symbols are as defined above with a compound of formula (IVi)R⁹OCH₂P⁺PPh₃ ⁻Hal  (IVi)  where R⁹ represents unsubstituted orsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups and Hal represents a halogen atom, to yield acompound of formula (IVj)

 where all symbols are as defined above, b) reacting the compound offormula (IVj) with a compound of formula R⁹OH where R⁹ is as defined inpart a to yield a, compound of formula (IVk),

 where all symbols are as defined above, and c) reacting a compound offormula (IVk) obtained above where all symbols are as defined above withtrialkylsilyl cyanide to produce a compound of formula (IVf) where allsymbols are as defined above.
 5. An intermediate of formula (IVg)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵and R⁶ when attached to carbon atom may be the same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl; orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylaminowhich may be mono or dialkylamino group, arylamino, acylamino,aralkylamino, arinoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylanino, carboxylic acid or itsamides, or sulfonic acid or its amides; W represents O; n is an integerranging from 1-4; Ar represents an unsubstituted or substituted divalentaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkylgroup; R¹⁰ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroaralkyl groups; and the linking group representedby —(CH₂)_(n)—O—may be attached either through nitrogen atom or carbonatom.
 6. A process for the preparation of compound of formula (IVg)

where X represents O or S; the groups R¹, R², R³, R⁴ and the groups R⁵and R⁶ when attached to carbon atom may be the same or different andrepresent hydrogen, halogen, hydroxy, cyano, nitro, formyl; orunsubstituted or substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, acyl, acyloxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, amino, alkylamninowhich may be mono or dialkylamnino group, arylamino, acylamino,aralkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, thioalkyl, alkylthio, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsamides, or sulfonic acid or its amides; W represents O; n is an integerranging from 1-4; Ar represents an unsubstituted or substituted divalentaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or unsubstituted or substituted aralkylgroup; R¹⁰ represents hydrogen or unsubstituted or substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroaralkyl groups; and the linking group representedby —(CH₂)_(n)—O—may be attached either through nitrogen atom or carbonatom, which comprises: a) reacting a compound of formula (III)

 where L¹ is a leaving group and all other symbols are as defined abovewith a compound of formula (IVm)

 where R⁸ is a hydrogen atom and all other symbols are as defined above,to yield a compound of formula (IVl)

 where R⁸ is a hydrogen atom and all other symbols are as defined above,and reacting the compound of formula (IVl) obtained above with anappropriate diazotizing agent.